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Atheroemboli to the lower urinary tract: a marker of atherosclerotic vascular disease--a case report. Atheroemboli to the lower genitourinary tract may serve as a marker for disseminated atheroembolic disease, a highly lethal condition. A case presentation and review of our institional experience is presented.

Intracoronary adenosine administration during reperfusion following 3 hours of ischemia: effects on infarct size, ventricular function, and regional myocardial blood flow. Previous studies have demonstrated that adenosine significantly enhances myocardial salvage after 90 minutes of regional ischemia. To determine its effect after prolonged ischemia, closed-chest dogs underwent 3 hours of left anterior descending artery occlusion followed by 72 hours of reperfusion. Intracoronary adenosine (3.75 mg/min; at 1.5 ml/min:total volume = 90 ml; n = 10) or an equivalent volume of saline (1.5 ml/min: total volume = 90 ml; n = 9) was infused into the left main coronary artery during the first 60 minutes of reperfusion. Regional myocardial blood flow was assessed serially with microspheres and regional ventricular function was assessed by contrast ventriculography. Infarct size was determined histologically. Light and electron microscopy were utilized to assess neutrophil infiltration and microvascular injury. Adenosine failed to reduce infarct size expressed as a percentage of the area at risk (38.0 +/- 4.9% versus 34.8 +/- 4.6%; p = NS) or to improve regional ventricular function as measured by the radial shortening method (3.2 +/- 1.8% versus 2.2 +/- 3.1%; p = NS) at 72 hours after reperfusion. Vasodilatory effects were not observed in the endo- and midmyocardial regions of the ischemic zone during adenosine administration. This was associated with a similar extent of capillary endothelial changes and neutrophil infiltration in both adenosine-treated and saline control groups. These results suggest that severe functional abnormalities are present in the vasculature after 3 hours of ischemia and that adenosine therapy is ineffective in enhancing myocardial salvage.

RAR-alpha gene rearrangements as a genetic marker for diagnosis and monitoring in acute promyelocytic leukemia. Acute promyelocytic leukemias (APLs) are characterized by a translocation that involves chromosomes 15 and 17. The translocation breakpoints have recently been identified and shown to involve the RAR-alpha gene on 17 and myl on 15. Here we report Southern blotting analysis of 26 APLs, including cases with normal karyotypes and atypical morphology, which showed RAR-alpha rearrangements in 92% cases, myl rearrangements in 73%, and either RAR-alpha or myl rearrangements in 100%. Despite a negative clinical and morphologic picture, DNA rearrangement analysis showed that neoplastic promyelocytes persisted in the bone marrow of two patients sampled after induction chemotherapy. Therefore, the RAR-alpha and myl rearrangements provide molecular markers for accurately diagnosing APLs and monitoring the course of the disease during and after chemotherapy.

The Framingham Disability Study: relationship of various coronary heart disease manifestations to disability in older persons living in the community. The relation between coronary heart disease and disability was examined in 2,576 community-dwelling women and men ages 55-88 years. These Framingham Study participants were originally recruited in 1948-51 for an examination of cardiovascular disease. Twenty-seven years later, remaining members of the cohort were interviewed to ascertain physical abilities, and a score on a disability scale was assigned. Multivariate logistic analyses examined disability in relation to uncomplicated angina pectoris (AP), complicated AP, and coronary heart disease other than AP, controlling for possible confounders. In younger and older women and men, uncomplicated and complicated AP were associated with disability. Coronary heart disease other than AP was associated with disability only in the younger men. Congestive heart failure predicted disability only in the women. These results suggest that onset of AP should be recognized as a critical point in the development of disability and that AP is a better predictor of disability than is myocardial infarction or coronary insufficiency.

Depression after acute myocardial infarction. The role of primary care physicians in rehabilitation. Depression is a common problem after myocardial infarction. Diagnosis is facilitated by use of the criteria for depression in the Diagnostic and Statistical Manual of Mental Disorders and self-rating questionnaires. Treatment may involve both psychological and pharmacologic interventions. The patient's medical status must be carefully assessed before administration of antidepressant medication. All antidepressants are contraindicated immediately after myocardial infarction. When signs and symptoms of depression are exhibited early in the recovery phase, alprazolam (Xanax) may offer advantages over more traditional antidepressants. Further research is necessary to determine the safety of newer antidepressants.

Safety and efficacy of thrombolytic therapy for superior vena cava syndrome The experience at the Cleveland Clinic from 1982 to 1990 using thrombolytic therapy for superior vena cava (SVC) syndrome was retrospectively reviewed. Sixteen patients, 11 of whom had indwelling central venous catheters, were treated with either urokinase (n = 11) or streptokinase (n = 5). Either urokinase (4,400 U/kg bolus followed by 4,400 U/kg/h) or streptokinase (250,000 U bolus followed by 100,000 U/h) was used, and venograms were performed before and after. Overall, 56 percent of patients had complete clot lysis and relief of symptoms. Thrombolytic therapy was effective in eight (73 percent) of 11 patients receiving urokinase and one (20 percent) of five patients receiving streptokinase. Of those with a central venous catheter, eight (73 percent) of 11 patients were successfully lysed, whereas only one (20 percent) of five patients was successfully lysed if no catheter was present. If thrombolytic therapy was performed less than or equal to five days of symptom onset, seven (88 percent) of eight patients were successful, if thrombolytic therapy was performed greater than five days after symptom onset, two (25 percent) of eight patients were successful. Symptoms were relieved and the catheter was preserved in patients in whom thrombolytic therapy was effective. Factors predicting success were as follows: (1) the use of urokinase compared with streptokinase; (2) the presence of a central venous catheter; and (3) a duration of symptoms less than or equal to five days.

Remote effect of deep-seated vascular brain lesions on cerebral blood flow. We measured regional cerebral blood flow using the xenon-133 inhalation method, at approximately 1 month after onset, in 60 stroke patients who had no evidence of major carotid artery stenosis or occlusion. Their single lesions (43 infarcts and 17 hematomas) were located in the capsulothalamolenticular region, sparing the cortex. Hemispheric mean cerebral blood flow was reduced on the side of the lesion in 25 patients and on both sides in 20. Regional hypoperfusion was observed in 46 patients (ipsilaterally in 34, bilaterally in 10, and contralaterally in two). Regional hypoperfusion was observed most frequently in the frontal lobe, particularly in the motor and premotor cortices of the prerolandic area. The 46 patients with regional hypoperfusion were compared with the 14 patients without regional hypoperfusion, considering the size and location of the lesion as well as the functional and analytic motor performances. As a rule, the lesion was slightly smaller and more posterior and the functional (p less than 0.001) and analytic (p less than 0.05) motor performances were significantly better in the 14 patients without regional hypoperfusion. Since the xenon-133 inhalation method examines cortical blood flow, we can attribute blood flow reductions resulting from deep-seated lesions to a functional depression akin to diaschisis. Interpretation of the clinical consequences and pathogenesis of this phenomenon requires further sequential and pathologic studies.

Assessment of brain death in children by means of P-31 MR spectroscopy: preliminary note. Work in progress. The authors examined the possibility of assessing cerebral damage with phosphorus-31 magnetic resonance (MR) spectroscopy in 24 patients (three infants, four children older than age 5 years, and 17 adults) who met the adult criteria for brain death. In all patients except patient 3 (an infant 8 months old), inorganic phosphate with phosphodiester was observed, and adenosine triphosphate (ATP) and phosphocreatine (PCr), which are detectable in healthy brains, were not detected. In 22 of these 23 patients, cardiac death occurred within 7 days after clinical brain death, and in one infant 14 months old, cardiac death occurred 38 days after clinical brain death. In patient 3, ATP and PCr were detected with P-31 MR spectroscopy, and now, more than 20 months after brain death, cardiac death has not yet occurred. In children younger than age 5 years, P-31 MR spectroscopic findings were predictive of the patient's clinical outcome. These findings may help establish criteria for the diagnosis of brain death in children younger than age 5 years.

Indomethacin responsive hypercalcaemia associated with a renal sarcoma. An infant presented with a non-metastatic renal spindle cell sarcoma and hypercalcaemia, which resolved after treatment with indomethacin. There was in vivo and in vitro evidence that hypercalcaemia was mediated by circulatory prostaglandins.

Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock. Although hemorrhage severely depresses macrophage functions, it is not known whether the increased TNF-alpha or PGE2 production is responsible for it. To study this C3H/HeN mice were bled to mean blood pressure of 35 mmHg for 60 minutes, resuscitated, and treated with either ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage increased plasma prostaglandin E2 (PGE2) levels by 151.7% +/- 40.0% (p less than 0.05) and significantly decreased peritoneal macrophage (pM phi) antigen presentation (AP) by 60.5% +/- 7.3%, Ia expression by 52.3% +/- 7.6%, and interleukin-1 (IL-1) synthesis by 60.5% +/- 12.3% compared to shams. However ibuprofen treatment reduced PGE2 plasma levels by 61.3% +/- 12.1% and significantly increased AP (+237.0% +/- 95.3%), Ia expression (+72.8% +/- 27.5%), IL-1 synthesis (+235.7% +/- 134.7%), and cachectin synthesis (+485.8% +/- 209.0%) compared to vehicle-treated animals. These results indicate that prostaglandins but not cachectin are involved in the suppression of pM phi functions following hemorrhage because blockade of prostaglandin synthesis improved depressed macrophage functions despite enhanced cachectin synthesis.

Spectral electroretinography in thioridazine toxicity. In three patients with thioridazine toxicity, the electroretinogram (ERG) to red light was found to be below the average normal range. A significant increase in its amplitude appeared with cessation of therapy in two cases. A further deterioration of the ERG amplitude to all stimulus conditions (white, blue, and red lights) occurred when the dose of the medication was increased in the third patient.

Surgery for Ebstein's anomaly: the clinical and echocardiographic evaluation of a new technique. Ten consecutive patients (age range 4 to 44 years, mean 22) underwent surgical repair of Ebstein's anomaly by vertical plication of the right ventricle and reimplantation of the tricuspid valve leaflets. No patient died during or after operation. Intraoperative postbypass echocardiography documented a good result in nine patients but severe tricuspid regurgitation in one patient, who then underwent prosthetic valve replacement during a second period of cardiopulmonary bypass. Two of four patients who had had right ventricular papillary muscle dysfunction in the early postoperative period showed improved papillary muscle function with concomitant reduction of tricuspid regurgitation 6 months later. All patients were evaluated clinically and by echocardiography 2 to 23 months later. All patients showed clinical improvement, seven by one functional class and three by two classes. All were in sinus rhythm. The mean cardiothoracic ratio decreased by 6% (p less than 0.05). On bicycle ergometry performed in six patients, peak oxygen consumption exceeded 20 ml/kg per min in five. Tricuspid regurgitation diminished in eight patients (by three grades in two patients, by two grades in five and by one grade in one patient); it remained unchanged in two. Comparison of preoperative and postoperative pulsed Doppler flow velocities across the pulmonary valve showed an increase in the peak velocity of flow across the valve (mean 83 +/- 14 versus 97 +/- 11 cm/s, p less than 0.005) and a decrease in the time to peak velocity (mean 130 +/- 16 versus 91 +/- 23 ms, p less than 0.05).

Usefulness of the electrophysiology laboratory for evaluation of proarrhythmic drug response in coronary artery disease. Two potential manifestations of proarrhythmic responses to type IA antiarrhythmic agents in the electrophysiology laboratory were evaluated in 122 patients with chronic coronary artery disease and previous myocardial infarction: (1) conversion of uniform nonsustained ventricular tachycardia (VT) into sustained VT after drug administration, and (2) induction of sustained VT by fewer extrastimuli after drug administration. Forty-two patients were evaluated for nonsustained VT. Eighty patients were evaluated for sustained VT: 30 of these had spontaneous sustained VT only while receiving empiric therapy with quinidine or procainamide, whereas the remaining 50 developed spontaneous VT in the absence of antiarrhythmic drugs. All patients underwent programmed stimulation in the baseline state and after procainamide. Four patients had conversion of induced uniform nonsustained VT into the same morphology, but sustained VT after procainamide administration. These responses only occurred in patients evaluated for nonsustained VT. Over 90% of patients presenting with sustained VT had uniform sustained VT induced at the baseline study and after procainamide, regardless of whether the spontaneous arrhythmia occurred only in the presence or absence of antiarrhythmic drugs. There was no significant difference in the change in mode of induction from baseline to procainamide study, regardless of whether patients had developed spontaneous VT only in the presence or absence of antiarrhythmic drugs. One patient with no inducible VT at the baseline study had inducible uniform sustained VT after procainamide administration, and 1 patient with inducible VT at baseline developed spontaneous sustained uniform VT after procainamide administration. Both patients had developed spontaneous sustained VT only while receiving therapy with type IA agents.

Differential protective effects of halothane and isoflurane against hypoxic and reoxygenation injury in the isolated guinea pig heart. The authors investigated the effects of halothane (HAL) and isoflurane (ISO) on cardiac depression produced by global hypoxia and the recovery of function following reoxygenation is isolated guinea pig hearts perfused with Krebs' solution at constant pressure. Isovolumetric left ventricular systolic (LVSP) and end-diastolic pressures (LVEDP) were measured by placing a saline filled, latex balloon into the left ventricle. Bipolar electrodes were placed in the right atrium and right ventricle for measurements of heart rate (HR), atrioventricular conduction time (AVCT), and determination of the incidence and severity of dysrhythmias occurring during hypoxia and reoxygenation. Hearts were divided into three groups: control (n = 20), halothane (n = 12), and isoflurane (n = 13). All hearts were exposed in sequence to oxygenated perfusate (PO2, 530 mmHg), moderately hypoxic perfusate (PO2, 91 mmHg) for 30 min, and then to oxygenated perfusate for 40 min. Halothane (1%, 0.4 mM) or isoflurane (1.5%, 0.5 mM) were administered 10 min before hypoxia, during hypoxia, and during the first 10 min of reoxygenation. Exposure to halothane and isoflurane before hypoxia produced a 14 and 11% decrease in heart rate, a 32 and 23% increase in AVCT, and a 47 and 28% decrease in LVSP (all P less than or equal to 0.001) for halothane and isoflurane, respectively, and no significant change in LVEDP. During hypoxia, HR decreased and AVCT increased similarly in both groups. Left ventricular systolic pressure (LVSP) decreased sharply with a narrowing of the prehypoxic differences among the groups. In the control and isoflurane groups, LVEDP increased during hypoxia but remained unchanged in the halothane group.

Lower eyelid retraction: a minimal incision surgical approach to retractor lysis. Lower eyelid retraction associated with prior blepharoplasty, trauma, or other conditions is a challenging problem for the ophthalmic surgeon. We describe a procedure involving tightening the lower eyelid and supraplacing the lateral canthus in combination with in-glove lysis of the lower eyelid retractors and scar tissue. This is accomplished through a small lateral incision. To date, we have treated over 200 eyelids using this technique with excellent results. We recommend this technique for the treatment of mild to moderate degrees of lower eyelid retraction.

Coagulation factor abnormalities as possible thrombotic risk factors after Fontan operations. Severe thromboembolism occurred in 3 of 37 patients who had undergone Fontan-type operations for correction of congenital heart defects several months to years after the operation. The patients were screened for coagulation factor abnormalities to find out whether known prothrombotic risk factors could explain the high frequency of thromboembolism. 63 abnormalities were found in 24 of the 37 patients. The commonest and most pronounced abnormality was deficiency of protein C, a known risk factor. Concentrations of antithrombin III and factors II and X were significantly lower in protein-C-deficient patients than in those with normal protein C concentrations. These findings suggest that the high thrombotic risk in these patients is caused or at least associated with an imbalance between procoagulant and anticoagulant factors.

Myocardial magnesium: relation to laboratory and clinical variables in patients undergoing cardiac surgery. Magnesium concentration was measured in the right atrial appendage of 100 patients undergoing cardiac surgery and associations with serum and mononuclear blood cell magnesium, other laboratory values and patient clinical variables were studied. In addition, magnesium was measured in the right atrial appendage and left ventricular free wall in 23 autopsy subjects to determine whether there was a proportional relation between right atrial appendage and left ventricular free wall magnesium. The mean left ventricular free wall/right atrial appendage magnesium ratio was 2.13 +/- 0.39 (r = 0.67, p = 0.0009). In the group with cardiac surgery, the right atrial appendage magnesium concentration correlated inversely with age (r = -0.54, p = 0.001). The mean right atrial appendage magnesium concentration (micrograms/g wet weight tissue) was lower in patients with postoperative cardiac arrhythmia than in those without arrhythmia (103 +/- 13 versus 111 +/- 10, p = 0.009) and in diabetic than in nondiabetic patients (103 +/- 13 versus 109 +/- 12, p = 0.02). The right atrial appendage magnesium concentration also tended to be lower in patients receiving potassium/magnesium-losing diuretics, although this difference did not achieve statistical significance (105 +/- 14 versus 109 +/- 11, p = 0.16). Right atrial appendage magnesium concentration correlated positively with serum creatinine concentration (r = 0.31, p = 0.002) and negatively with serum calcium concentration (r = -0.29, p = 0.013). Serum magnesium did not correlate with right atrial appendage or mononuclear blood cell magnesium concentration or clinical variables. There was a statistically significant correlation between mononuclear blood cell and right atrial appendage magnesium concentrations in some subgroups of patients.

Acute reduction of mitral valve area after percutaneous balloon mitral valvuloplasty: assessment with Doppler continuity equation method. Mitral valve areas before and after balloon mitral valvuloplasty were serially determined by the Doppler continuity equation method in 16 patients. Ultrasound examinations were performed before and immediately after balloon inflation and 24 hours, 1 week, and 1 month after valvuloplasty. Mitral valve area determined by the Doppler continuity equation method correlated well with that determined at catheterization by the Gorlin formula, not only before but also immediately after balloon inflation (y = 0.87 x + 0.05, standard error of estimate = 0.22 cm2, r = 0.90). Serial calculation of mitral valve area by the Doppler continuity equation method showed a slight but significant decrease in the valve area at 24 hours after balloon mitral valvuloplasty but no change after that. We conclude that the Doppler continuity equation method provides an accurate estimation of mitral valve area before and even after balloon valvuloplasty. Mitral valve area dilated by balloon inflation is decreased slightly within 24 hours after the procedure, which corroborates valve stretch as one mechanism for increasing mitral valve area with balloon valvuloplasty. Estimation of mitral valve area immediately after balloon mitral valvuloplasty may overestimate the long-term efficacy of the procedure.

Idiopathic and symptomatic trigeminal pain. The trigeminal reflexes (corneal reflex, blink reflex, masseter inhibitory periods, jaw-jerk) and far field scalp potentials (nerve, root, brainstem, subcortical) evoked by percutaneous infraorbital stimulation were recorded in 30 patients with "idiopathic" trigeminal neuralgia (ITN) and 20 with "symptomatic" trigeminal pain (STP): seven postherpetic neuralgia, five multiple sclerosis, four tumour, two vascular malformation, one Tolosa-Hunt syndrome, and one traumatic fracture. All the patients with STP and two of those with ITN had trigeminal reflex abnormalities; 80% of patients with STP and 30% of those with ITN had evoked potential abnormalities. The results indicate that 1) trigeminal reflexes and evoked potentials are both useful in the examination of patients with trigeminal pain, and in cases secondary to specific pathologies provide 100% sensitivity; 2) in "symptomatic" and "idiopathic" paroxysmal pain the primary lesion affects the afferent fibres in the proximal portion of the root or the intrinsic portion in the pons; 3) primary sensory neurons of the A-beta fibre group are involved in both paroxysmal and constant pain, but in the latter the damage is far more severe.

Unusual aspects of aortovenous fistulas associated with ruptured abdominal aortic aneurysms. Three unusual cases of an abdominal aortic aneurysm spontaneously rupturing into the retroperitoneum and an adherent posterior vein are reported. No patient demonstrated signs or symptoms of an aortovenous fistula before surgery. Emergent surgery prevented extensive preoperative diagnostic testing. The three abdominal aortic aneurysms were very large and averaged 13 cm in diameter. One fistula involved an inflammatory aneurysm, which is the fifth such case reported. The aortic fistulas were to the inferior vena cava (158 other cases reported in the English-language literature), a left renal vein (16 other cases reported), and an iliac vein (7 other cases reported). Routine use of the cell-saver, oversewing of the fistula from within the aneurysm, and a heightened awareness that this unusual complication is more common in the presence of a very large, ruptured abdominal aortic aneurysm should improve survival.

Acute hypervolaemia increases gastroduodenal resistance to the flow of liquid in the rat. The effect of volume expansion of extracellular fluid on gastroduodenal resistance to the flow of isotonic saline was assessed in three groups of rats using intravenous infusions of isotonic, isotonic-isoncotic, and isotonic-isoncotic-isohaemic solutions. The gastroduodenal segment of 29 male Wistar rats was barostatically perfused at a constant pressure gradient of 4 cm H2O and changes in flow (ml/minute) were taken as a reflection of changes in gastroduodenal resistance. Isotonic expansion led to a 33% drop in gastroduodenal flow compared with the normovolaemic period in the same animals (p less than 0.01). Extracellular fluid expansion with isotonic-isoncotic and isotonic-isoncotic-isohaemic solutions was associated with reductions in gastroduodenal flow of 29% (p less than 0.05) and 31% (p less than 0.01) respectively. The increase in gastroduodenal resistance is due to hypervolaemia per se and not to haemodilution, decreases in plasma oncotic pressure, or electrolyte imbalance. The effect of hypervolaemia on gastroduodenal resistance, which was reversed by small haemorrhages (0.5-1.0 ml per 100 g body weight), may be due to changes in tonus or phasic motor activity, or both, and may be part of the homeostatic processes that help the organism minimise liquid volume excess.

Progress and challenges in psychosocial and behavioral research in cancer in the twentieth century. Research in the psychosocial and behavioral aspects of cancer has shown steady growth since the 1950s, and its course of development has paralleled the history of medical techniques in treating cancer. Table 1 outlines this parallel evolution from the 1850s to the 1960s. The roles of the American Cancer Society and the National Cancer Institute (NCI) in spearheading and nurturing research in this area are documented. Interest in psychooncologic questions can be traced back for centuries to the search for etiologic factors and psychologic variables that would explain individual vulnerability to cancer. The first psychologic studies of cancer patients were reported in 1951 and 1952 from the Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center, respectively. The 1970s saw new interest in psychosocial and behavioral research with many issues being addressed for the first time: better care of the terminally ill through more humanistic approaches including better means of pain control; ethical concerns related to patient rights and their status as subjects in experimental protocols; trying to measure quality of life for cancer patients on protocols; seeing the need for multidisciplinary collaborative groups to make up for the absence of formal training in this area; and the need to design valid, accurate measuring scales specific to the symptomology of patients with cancer. Table 4 outlines how the 1980s gave increasing recognition and support to the psychosocial dimensions of cancer. This period produced a series of key conferences that examined a broad research and education perspective and produced recommendations that remain a benchmark in regard to instrumentation, conceptual models, pitfalls of psychosocial research, training, and education, and the organization of research efforts. New precision has been added to the field in the past 6 years: studies measuring concurrent psychologic, endocrine, and immune function; use of statistical modeling to incorporate quality of life data as a correction factor in survival data (TWiST and QALY); and broadened definitions of medical outcome to include functional status, thus allowing advances in psychiatric measurements to help answer questions in cancer. The challenges for the 1990s are identified in a summary in Table 9. Especially noteworthy is the observation that the comprehensive research needed today cannot be carried out by any one discipline alone. New approaches call for areas of the social sciences formerly inactive in cancer research (e.g., anthropology) to contribute the tools and expertise required to address the problems.

Long-term morphology of spastic or flaccid muscles in spinal cord-transected rabbits. Despite difficulty in long-term maintenance of spinalized rabbits, muscular pathologic changes in chronic spinalized rabbits could be observed for a period of four weeks. Rabbits were prepared by spinal cord transection at T10 (spastic paralysis) or by spinal cord removal below L7 (flaccid paralysis). Spastic preparations showed hind-limb spasticity and reflex incontinence one to two days after operation. Hypertrophic fibers began to appear in spastic muscles after two weeks. This hypertrophy, thought to be caused by phasic repetitive contraction, was verified by electron microscopy to be different from normal exercise hypertrophy. Flaccid preparations maintained hind-limb flaccidity and overflow incontinence. In flaccid muscle, marked muscle fiber necrosis indicated rapid atrophy. Spinal deformity and joint contracture inactivate spinalized rabbits, and cause pressure sores. However, feeding assistance and avoidance of complications make long-term maintenance possible.

Anorexia in older patients: its meaning and management. In the elderly, clinically significant weight loss is closely related to malnutrition, the causes of which can proliferate in this age group. Clinicians must therefore keep a wide range of possible etiologies in mind when evaluating these patients. These fall into the general categories of social, psychological, medical, and age-related. Isolating the cause will direct what is often simple, effective, and, perhaps, life-saving therapy.

Captopril renography in the diagnosis of renal artery stenosis: accuracy and limitations. PURPOSE: The purpose of this study was to determine the sensitivity, specificity, and clinical usefulness of renography performed in combination with captopril administration ("captopril renography") in diagnosing renal artery stenosis. PATIENTS AND METHODS: Fifty-five patients with suspected renal artery stenosis underwent renography prior to performance of renal angiography. Renography was performed on two consecutive days using technetium-99m-diethylenetiamine pentaacetic acid (DTPA) as an index of glomerular filtration rate and iodine-131-orthoiodohippurate (OIH) as an index of renal blood flow. Captopril (25 mg orally, crushed) was administered 1 hour before the second study. Renal artery stenosis was defined as a stenosis exceeding 70%. Renographic criteria were then established, retrospectively, to differentiate renal artery stenosis from essential hypertension based on (1) asymmetry of function and (2) the presence of captopril-induced changes. RESULTS: Renal artery stenosis was detected in 35 of 55 patients (21 with unilateral and 14 with bilateral stenosis). Three criteria were established for diagnosing renal artery stenosis: (1) a percent uptake of DTPA by the affected kidney of less than 40% of the combined bilateral uptake, (2) a delayed time to peak uptake of DTPA, which was more than 5 minutes longer in the affected kidney than in the contralateral kidney, (3) a delayed excretion of DTPA, with retention at 15 minutes, as a fraction of peak activity, more than 20% greater than in the contralateral kidney. The presence of one or more of these criteria was diagnostic of renal artery stenosis, with a sensitivity and specificity of 71% and 75%, respectively before captopril administration, and 94% and 95% after captopril administration. Lesser degrees of asymmetry (i.e., uptake of 40% to 50%) had very poor diagnostic specificity. Among patients with bilateral stenoses, asymmetry identified the more severely affected kidney, but the presence or absence of stenosis in the contralateral kidney could not be reliably determined. When pre- and post-captopril studies were compared, the presence of captopril-induced scintigraphic changes was a highly specific finding for renal artery stenosis, but occurred in only 51% of the cases. OIH scintigraphy provided similar results, with slightly lower sensitivity and specificity. CONCLUSION: Asymmetry of DTPA uptake, time to peak uptake, or retention seen on a single post-captopril renogram is a highly sensitive and specific finding in detecting renal artery stenosis but does not distinguish unilateral from bilateral disease. If renograms are obtained both before and after captopril administration, the presence of captopril-induced change is a highly specific finding for the detection of renal artery stenosis, but the sensitivity of this finding is low.

Continuous postoperative regional analgesia by nerve sheath block for amputation surgery--a pilot study. A pilot study of continuous postoperative regional analgesia by nerve sheath block for lower limb amputation is presented. At the time of exposure of sciatic or posterior tibial nerve trunks during above- or below-knee amputations in 11 patients with ASA physical status III or IV, a catheter was introduced directly into the transected nerve sheath for continuous infusion of 0.25% bupivacaine at a rate of 10 mL/h for 72 h. Effective amputation stump analgesia was obtained, significantly reducing the need for on-demand narcotic analgesics during this time to a mean dose equivalent of 1.4 mg of morphine compared with a retrospective control group who received the equivalent of a mean dose of 18.4 mg of morphine (P less than 0.0001). No complications related to the technique were observed. A follow-up of the group receiving continuous postoperative regional analgesia for up to 12 mo showed a total absence of phantom pain despite the presence of preoperative limb pain.

Alanine-based oral rehydration therapy for infants with acute diarrhea. Twenty male infants less than 1 year of age with acute diarrhea and dehydration were randomly assigned to a study group and studied in blind fashion in a metabolic unit to assess the efficacy of the addition of 30 mmol/L alanine to the standard World Health Organization (WHO) oral rehydration solution (ORS). Patients were exclusively rehydrated with one of two types of ORS during the first 24 hours of treatment. On the second day, oral feedings were started with a lactose-free formula, and ORS was given to replace stool losses. Body weight, ORS, food intake, vomitus, stool, and urine output were recorded at 6-hour intervals. Blood was drawn at the time of admission, after rehydration, and at 24 and 48 hours of hospitalization to monitor blood gases and electrolytes. Rehydration was satisfactory in both groups of patients. ORS that contained alanine did not reduce the purging rates of the infants compared with those who received standard ORS. Clinically no adverse effect of the alanine-based ORS was observed during hospitalization. None of the patients had significant hypernatremia or hyponatremia, and serum amino acid levels were not altered. These data show that the addition of 30 mmol/L alanine to the standard WHO-ORS produces no further improvement in the outcome of the infants with acute diarrhea compared with those fed the standard WHO-ORS.

Improving outcomes of analgesic treatment: is education enough? Frequent undertreatment of analgesic-responsive acute pain and chronic cancer pain persists, despite intensive efforts to provide clinicians with information about analgesics. A set of background factors must be addressed in interventions to improve pain treatment: Traditional patterns of clinician and patient interaction on the ward, quality assurance, and drug regulatory practices do not support prompt recognition and treatment of pain. Possible interventions to modify these patterns of daily practice include monitoring and displaying patient pain ratings routinely, making available educational tools to assist optimal drug ordering, encouraging patients to communicate about unrelieved pain, reviewing quality assurance of pain treatment regimens, increasing behavioral research into analgesic prescribing, and selectively modifying narcotics regulatory practices.

Role of new antiplatelet agents as adjunctive therapies in thrombolysis. Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion.

Determinants and significance of diltiazem plasma concentrations after acute myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group. A total of 1,975 plasma diltiazem concentrations were obtained from 1,067 patients enrolled in a multicenter secondary intervention study of diltiazem after acute myocardial infarction. To evaluate the determinants and significance of diltiazem concentrations in this patient population, we related drug concentrations to a variety of clinical variables recorded on the case history forms. Multiple linear regression analysis showed that (1) time from the last drug dose, (2) drug dose taken, (3) patient height (an index of lean body weight), and (4) patient age were important determinants of plasma concentration. For an equivalent dose, plasma diltiazem concentrations in a 75-year-old patient were about double those of a 25-year-old patient. Total weight and drug dose prescribed did not significantly affect plasma concentrations. Whereas drug concentrations were higher (p = 0.01) among patients with left-sided heart failure, they were not altered by renal dysfunction, hepatic disease or beta blockers. Diltiazem concentrations were a significant determinant of diastolic arterial pressure (p less than 10(-9), but neither systolic pressure nor heart rate were significantly related to diltiazem concentration. The overall incidence of adverse experiences was not related to drug concentrations, but the occurrence of second- and third-degree atrioventricular block in the coronary care unit and the need for a temporary pacemaker were substantially higher among patients with a drug concentration greater than 150 ng/ml (7.4 and 1.9%, respectively) than among patients with lower concentrations (2.6% for atrioventricular block, 0.3% for pacemaker; p = 0.02 for each). The risk of atrioventricular block was particularly increased by high diltiazem concentrations in the face of acute inferior infarction. These results suggest that diltiazem's pharmacologic and clinical effects in a large population are concentration-related, and that the consideration of patient size, age, and left ventricular function in selecting a diltiazem dose may allow for effective drug therapy with a reduced likelihood of adverse effects.

Role of prostanoids in renin-dependent and renin-independent hypertension. We investigated the role of prostanoid-mediated pressor mechanisms in setting the level of blood pressure in renin-dependent and renin-independent models of hypertension in unanesthetized rats. Intravenous administration of a blocker of thromboxane A2/prostaglandin endoperoxide receptors, SQ29548 (2 mg/kg bolus injection plus 2 mg/kg/hr for 3 hours), reduced from 162 +/- 4 to 144 +/- 5 mm Hg (p less than 0.05) the blood pressure of rats with aortic coarctation-induced hypertension at 7-14 days after coarctation when plasma renin activity is greatly increased. In contrast, treatment with SQ29548 was without effect on the blood pressure of either normotensive or hypertensive rats (i.e., aortic coarctation-induced hypertension at 90-113 days after coarctation, deoxycorticosterone-salt-induced hypertension) having normal or depressed values of plasma renin activity. The blood pressure-lowering effect of SQ29548 in the early phase of aortic coarctation-induced hypertension was positively correlated with the prevailing plasma renin activity and could not be demonstrated in hypertensive rats pretreated with indomethacin. We attribute the hypotensive effect of SQ29548 to interference with pressor mechanisms that depend on activation of thromboxane A2/prostaglandin endoperoxide receptors and suggest that such prostanoid-mediated mechanisms are operational and contribute to an increase in blood pressure in angiotensin-dependent forms of hypertension. Also prostanoid-mediated vasodepressor mechanisms are operational in the early phase of aortic coarctation-induced hypertension since the blood pressure of rats pretreated with SQ29548 was increased by the subsequent administration of indomethacin. Accordingly, the blood pressure of rats with aortic coarctation-induced hypertension is influenced by the interplay of prostanoid-mediated pressor and vasodepressor mechanisms.

Treatment of advanced neuroblastoma with I-131 meta-iodobenzylguanidine. From February 1986 to December 1988, 31 children with advanced pretreated neuroblastoma were treated with 131-I meta-Iodobenzylguanidine (131-MIBG). Thirteen children had been resistant to first-line therapy, three had suffered a local relapse, and fourteen had suffered a disseminated relapse without over bone marrow infiltration. One child was treated initially because of resistance to first-line therapy, and subsequently for a local relapse. A total of 72 courses of 131-MIBG was administered, with doses ranging from 2.8 to 6.0 GBq (median, 3.7 GBq). One child received five courses, two four courses, 13 three courses, four two courses, and 12 one course of 131-MIBG. The most common toxic effect was thrombocytopenia, with a platelet level of less than 50,000/cmm occurring after 19 of 60 evaluable courses. A leukocyte count less than 1000/cmm was seen only once. There were six major responses (two complete) lasting 4 to 9 months, and two minor responses lasting longer than 38 and 44 months. Responses were seen more commonly in children whose only lesion was a residual primary tumor and in children who had not been pretreated who experienced disseminated relapse. Further studies of the role of 131-I meta-Iodobenzylguanidine in treatment of neuroblastoma are needed.

Oral contraception in disease states. Oral contraceptives are clearly contraindicated in patients with a history of thromboembolic disease, ischemic heart attack, or cerebral stroke. Patients requiring long-term anticoagulant treatment can be treated with gonadotropin-releasing hormone analogs to prevent ovulation, because ruptured follicles can cause massive intraperitoneal bleeding. Patients with essential hypertension and severe liver diseases should also discontinue treatment 4 weeks before major elective surgery. Migraine and diabetes mellitus are regarded as relative contraindications, depending on the individual situation. Long-term diseases, such as Crohn's disease, epilepsy, and sickle cell anemia, also require individualized consultation.

Role of dipyridamole-echocardiography test in the evaluation of coronary reserve after coronary artery bypass grafting. The object of this study was to assess the usefulness of the dipyridamole-echocardiography test in the early evaluation of coronary artery bypass grafting, when the use of an exercise stress test is precluded. We studied 39 consecutive patients (37 men and two women, mean age 57.3 years) referred to our institute for elective coronary artery bypass. Five patients had single, 12 patients double, 20 patients triple vessel disease, and two had left main stem disease. Nineteen left internal mammary artery grafts, 20 sequential grafts, and 39 single vein grafts were performed. All the patients were subjected to the test before (time range 1 to 3 days) and after (time range 6 to 10 days) the operation in the absence of therapy. Dipyridamole was administered intravenously 0.56 mg/kg over 4 minutes (low dose); if no effect was apparent, an additional 0.28 mg/kg over 2 minutes (high dose) was given. During the test, blood pressure and a twelve-lead electrocardiogram were monitored. An arbitrary wall motion score was derived by dividing the left ventricle into six regions and grading from 0 to 3-normokinetic, hypokinetic, akinetic, and dyskinetic zones. Preoperatively the test was positive in 38 patients as evidenced by wall motion abnormalities (36 patients had electrocardiographic changes) and in one patient by electrocardiographic changes and chest pain; 22 tests were positive after the low dose and 17 after the high dose. Angina was present in 33 patients. Mean wall motion score was 1.64 per patient in the basal condition and 4.03 per patient after the test (p less than 0.001). After coronary bypass in three patients the test was positive at the same dosage that was used preoperatively, as shown by wall motion abnormalities (in two patients by electrocardiographic changes, as well). Four patients had symptoms. Furthermore, at 6 months' follow-up, a treadmill stress test performed in these three patients was positive for ischemia and angina. The wall motion score was 1.25 per patient in the basal condition and 1.53 per patient after the test (no significant difference). When the preoperative wall motion score obtained after dipyridamole echocardiography was compared with the postoperative score, a statistically significant difference was seen: 4.03 per patient versus 1.53 per patient (p less than 001). In eight patients we observed an improvement of basal myocardial contractility after the operation, which indicates the reversibility of wall motion abnormalities observed before coronary bypass. In conclusion our data show that the dipyridamole-echocardiography test is a suitable method for the early assessment of bypass grafting when other methods, exercise dependent, are not indicated.(ABSTRACT TRUNCATED AT 400 WORDS).

Creutzfeldt-Jakob disease in pituitary growth hormone recipients in the United States. To assess the magnitude of Creutzfeldt-Jakob disease (CJD) occurrence among recipients of pituitary-derived human growth hormone (HGH), we conducted an epidemiologic follow-up of 6284 recipients of HGH distributed through the National Hormone and Pituitary Program. Seven neuropathologically confirmed cases of CJD have occurred in this population to date: six patients with clinical CJD presented with ataxia and imbalance, rather than with altered mentation, which is the most common initial manifestation in sporadic CJD, and one patient died in the preclinical incubation state of the disease. All seven cases occurred among the nearly 700 HGH recipients who started therapy before 1970. Since only 10% of the cohort has been followed up for the 15-year average incubation interval from midpoint of HGH treatment to onset of symptoms, the great majority of potentially exposed patients have not yet attained the requisite incubation period for expression of CJD. The median duration of HGH therapy of 100 months in the CJD cases was significantly longer than 41 months for all patients starting treatment before 1970; thus, the duration of pituitary HGH therapy is a major risk factor for CJD.

Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease BACKGROUND. The maintenance of cellular levels of high-energy phosphates is required for myocardial function and preservation. In animals, severe myocardial ischemia is characterized by the rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP. METHODS. To determine whether ischemic metabolic changes are detectable in humans, we recorded spatially localized phosphorus-31 nuclear-magnetic-resonance (31P NMR) spectra from the anterior myocardium before, during, and after isometric hand-grip exercise. RESULTS. The mean (+/- SD) ratio of phosphocreatine to ATP in the left ventricular wall when subjects were at rest was 1.72 +/- 0.15 in normal subjects (n = 11) and 1.59 +/- 0.31 in patients with nonischemic heart disease (n = 9), and the ratio did not change during hand-grip exercise in either group. However, in patients with coronary heart disease and ischemia due to severe stenosis (greater than or equal to 70 percent) of the left anterior descending or left main coronary arteries (n = 16), the ratio decreased from 1.45 +/- 0.31 at rest to 0.91 +/- 0.24 during exercise (P less than 0.001) and recovered to 1.27 +/- 0.38 two minutes after exercise. Only three patients with coronary heart disease had clinical symptoms of ischemia during exercise. Repeat exercise testing in five patients after revascularization yielded values of 1.60 +/- 0.20 at rest and 1.62 +/- 0.18 during exercise (P not significant), as compared with 1.51 +/- 0.19 at rest and 1.02 +/- 0.26 during exercise before revascularization (P less than 0.02). CONCLUSIONS. The decrease in the ratio of phosphocreatine to ATP during hand-grip exercise in patients with myocardial ischemia reflects a transient imbalance between oxygen supply and demand in myocardium with compromised blood flow. Exercise testing with 31P NMR is a useful method of assessing the effect of ischemia on myocardial metabolism of high-energy phosphates and of monitoring the response to treatment.

Detection of circulating candida enolase by immunoassay in patients with cancer and invasive candidiasis BACKGROUND. Invasive candidiasis is a major nosocomial infection that is difficult to diagnose. Few biochemically defined markers of invasive candidiasis are known. Initial findings suggested that the presence of candida enolase in the blood may be a novel marker for invasive candidiasis. METHODS. We tested 170 patients at high risk for invasive candidiasis for candida enolase antigenemia. All the patients had cancer and neutropenia. We detected antigen using a double-sandwich liposomal immunoassay for candida enolase in serially collected serum samples. Invasive candidiasis was proved by finding candida species in deep nonmucosal tissue, blood cultures, or both. Antigen testing was performed with the investigator blinded to tissue or culture diagnosis. RESULTS. Among 24 patients with proved invasive candidiasis, 149 serum samples were tested for enolase antigenemia; 80 were positive and 69 negative (sensitivity per sample, 54 percent). Multiple sampling improved the detection of antigenemia, which was found in 11 of 13 proved cases of deep tissue infection (85 percent) and in 7 of 11 proved cases of fungemia (64 percent). Specificity was 96 percent as measured against control groups including patients with mucosal colonization, bacteremia, and other deep mycoses. Antigenemia was detected in the absence of fungemia in 5 cases of deep tissue candidiasis, but was not detected in 6 cases of fungemia alone. CONCLUSIONS. Candida enolase antigenemia is a novel marker for invasive candidiasis. It may be a useful indicator of deep infection in patients with cancer and neutropenia and may complement the diagnostic usefulness of blood cultures.

Clonotypic analysis of anti-acetylcholine receptor antibodies from experimental autoimmune myasthenia gravis-sensitive Lewis rats and experimental autoimmune myasthenia gravis-resistant Wistar Furth rats. A single immunization of Lewis rats with purified acetylcholine receptor (AChR) emulsified in adjuvant typically stimulates the production of oligoclonal AChR-reactive antibodies (as demonstrated by IEF) dominated by the IgG2a subclass, of moderate but clonotypically heterogeneous relative Ag-binding avidity, and capable of inducing symptoms of experimental autoimmune myasthenia gravis. Although similar immunization of Wistar Furth rats produces AChR-reactive antibodies with similar characteristics of clonotypic heterogeneity, avidity, and isotype expression, no detectable signs of AChR-dependent muscle impairment is observed. This contrasts the ability to induce impaired AChR function upon the passive transfer of pre-formed Lewis anti-AChR antibodies into naive Wistar Furth rats, suggesting that disease resistance in this model is not conferred at the level of the AChR itself. Moreover, if more aggressive immunization protocols are used (i.e., multiple injections of AChR), a transient breakthrough of AChR-dependent muscle dysfunction can be induced directly in the Wistar Furth strain indicating that the potential for the production of disease-causing antibodies does exist in the Wistar Furth repertoire. IEF analysis of Wistar Furth anti-AChR antibodies has revealed that hyperimmunization results in modified antibody clonotype expression that might explain changing expression of disease symptoms; however, explanations for the apparent "resistance" of Wistar Furth rats to disease induction are likely to be complex.

An implantable neurocybernetic prosthesis system. The neurocybernetic prosthesis (Cyberonics, Inc.) is an implantable, multiprogrammable pulse generator that delivers constant current electrical signals to the vagus nerve for the purpose of reducing the frequency and/or severity of epileptic seizures. The device is implanted in a subcutaneous chest pocket just below the clavicle, similar to cardiac pacemaker placement. The stimulation signal is transmitted from the prosthesis to the vagus nerve through a stimulation lead. The prosthesis can be programmed using any IBM-compatible personal computer with programming software and a programming wand. The electrodes used in the first group of patients were found to break at an unacceptable rate. Design modifications appear to have resolved this problem.

Sinus nodal dysfunction in young patients with long QT syndrome. Although sinus bradycardia and low heart rate with exercise have been found in some patients with long QT syndrome, systematic evaluation, including intracardiac electrophysiologic (EPS) tests of sinus node function, has not been reported. Records were reviewed of 14 children and adolescents (age 3 to 16 years) with long QT syndrome (mean QTc 0.51 second) who underwent noninvasive testing and intracardiac EPS because of syncope or cardiac arrest. The resting electrocardiographic (ECG) sinus heart rate was low for age in only 1 of 13 patients, while the lowest Holter-monitored sinus heart rate was abnormal in 4 of 12. The maximum exercise heart rate was abnormally low in 6 of the 12 who underwent exercise testing. For the EPS tests, the corrected sinus node recovery time (CSNRT) was long in 8 of 14 and the sinoatrial conduction time (SACT) was long in six of the nine in whom it was calculable. When both noninvasive and EPS indices are considered, 13 of the 14 patients had some type of sinus node dysfunction.

Interpleural analgesia after thoracotomy. We examined the effects of the following variables on interpleural analgesia after thoracotomy: addition of epinephrine to local anesthetic, thoracostomy drainage, two-catheter placement, and location of catheter tips. Twenty patients were randomized to have one catheter (paravertebral tip location) or two catheters (paravertebral and lateral thoracic wall tip locations). Interpleural catheters were sutured to the parietal pleura by the surgeon at time of wound closure. Patients were then randomly assigned to receive 20 mL of 0.5% bupivacaine with 1:200,000 epinephrine through the single catheter or 10 mL of 0.5% bupivacaine with or without 1:200,000 epinephrine through each of the two catheters while supine. Bupivacaine concentrations in whole blood and in thoracostomy drainage fluid were assayed by gas chromatography. Actual content of bupivacaine in the drainage fluid was calculated. Degree of analgesia was assessed by verbal numerical pain scores over the first 4 h and opioid demand thereafter. Addition of epinephrine to bupivacaine did not influence the degree of analgesia. Approximately 30%-40% of any administered dose of bupivacaine was lost via the thoracostomy tube over a 4-h period. There was no correlation between the true initial dose (100 mg minus thoracostomy drainage) and Cmax. Use of two catheters resulted in significantly less opioid requirements after an initial 8-h period. Failure to achieve adequate interpleural analgesia in postthoracotomy patients may be related to loss of anesthetic via thoracostomy drainage, presence of extravasated blood and tissue fluid in the pleural space, and possibly sequestration and channeling of flow of local anesthetic by restricted motion of an operated lung.

Chondrosarcoma of the head and neck. Chondrosarcoma is a malignancy rarely encountered in the head and neck. In an attempt to define this tumor's characteristics and response to therapy, all cases of chondrosarcoma treated at the University of Michigan over the past 25 years were retrospectively studied. Fourteen cases originating in the nose and paranasal sinuses, mandible, temporal bone, and larynx were reviewed. Aggressive surgical resection was the mainstay of treatment, and resulted in an overall survival of 70%, with an average follow-up of 3.5 years. Survival was highest in primary temporal bone lesions, and lowest in paranasal sinus lesions. Unresectable lesions were not cured by other modalities. This study, therefore, continued to support the crucial role of wide surgical resection in the treatment of head and neck chondrosarcoma, but conservative resection, when needed to preserve important structures, has resulted in long-term survival.

Zollinger-Ellison syndrome. Relation to Helicobacter pylori-associated chronic gastritis and gastric acid secretion. Since Helicobacter pylori infects the gastric mucosa in most patients with chronic duodenal ulcer, infection with this organism has been implicated in the pathogenesis of this common disease. We postulated that if H. pylori is pathogenic in the usual type of duodenal ulcer, it should be less common when duodenal ulcer has another, specific etiology, such as Zollinger-Ellison syndrome. Gastric mucosa was compared from 18 patients with proven Zollinger-Ellison syndrome (17 of whom had had duodenal ulcer disease) and 18 controls with chronic duodenal ulcer without such a diagnosis. All subjects, who were matched for age and sex, had undergone elective gastric resections. Gastric tissues were stained by hematoxylin-eosin and Giemsa and were reviewed by an experienced pathologist who was unaware of the diagnosis. The frequency of H. pylori in patients with Zollinger-Ellison syndrome (8/18) was lower than in controls with duodenal ulcer (16/18; P less than 0.02). Moreover, chronic antral gastritis scores were higher in patients with duodenal ulcer (P less than 0.01). In Zollinger-Ellison syndrome, peak acid output was lower in patients positive (median 22 meq/30 min) compared to those negative for H. pylori (median 32 meq/30 min; P less than 0.02) but serum gastrin was correspondingly lower in patients positive for H. pylori (P less than 0.05). H. pylori infection appears to be more frequent when duodenal ulceration is not associated with another etiology, such as acid hypersecretion in Zollinger-Ellison syndrome. H. pylori infection in Zollinger-Ellison syndrome may also be associated with decreased gastric acid secretion.

cDNA cloning and sequencing of human fibrillarin, a conserved nucleolar protein recognized by autoimmune antisera. We have isolated a 1.1-kilobase cDNA clone that encodes human fibrillarin by screening a hepatoma library in parallel with DNA probes derived from the fibrillarin genes of Saccharomyces cerevisiae (NOP1) and Xenopus laevis. RNA blot analysis indicates that the corresponding mRNA is approximately 1300 nucleotides in length. Human fibrillarin expressed in vitro migrates on SDS gels as a 36-kDa protein that is specifically immunoprecipitated by antisera from humans with scleroderma autoimmune disease. Human fibrillarin contains an amino-terminal repetitive domain approximately 75-80 amino acids in length that is rich in glycine and arginine residues and is similar to amino-terminal domains in the yeast and Xenopus fibrillarins. The occurrence of a putative RNA-binding domain and an RNP consensus sequence within the protein is consistent with the association of fibrillarin with small nucleolar RNAs. Protein sequence alignments show that 67% of amino acids from human fibrillarin are identical to those in yeast fibrillarin and that 81% are identical to those in Xenopus fibrillarin. This identity suggests the evolutionary conservation of an important function early in the pathway for ribosome biosynthesis.

Feasibility of intraoperative cytodiagnosis of lung cancer. Of 354 thoracotomies, 114 cases involved intraoperative cytopathologic evaluation. The study included 86 men and 28 women, and 184 specimens were examined. Smears were taken from the lung lesion or lymph node and the chest wall or bronchial stump by imprint or needle aspiration. Intraoperative evaluations were compared with histologic findings. In 85 cases not diagnosed as malignant preoperatively, malignancy was confirmed in 97.6 percent of cases and histologic type in 71.8 percent. In the 28 cases diagnosed as malignant preoperatively, there was only one false-negative. The most important finding during thoracotomy is whether a lesion is malignant or not. The time required to obtain a pathologic diagnosis also is important. We are able to obtain the results of a cytologic diagnosis within 10 min. Cytologic diagnosis of malignancy during thoractomy may be a feasible and convenient method of diagnosis, especially where malignancy is suspected.

Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome We retrospectively analyzed the outcome of all patients who received their primary treatment for follicular thyroid cancer at the Mayo Clinic between 1946 and 1970. The diagnosis was confirmed by reexamination of preserved tissue specimens. The 57 female and 43 male patients (mean age, 53 years) underwent follow-up for a maximum of 32 years (mean, 17.4 years). All patients were treated surgically, and total removal of primary tumor was thought to have been accomplished in all but three. Only 2 of the 88 patients without distant metastatic lesions at the time of initial diagnosis underwent ablation of the thyroid remnant. At the conclusion of the study, 52 patients had died, thyroid cancer being the cause of death in 19. On the basis of univariate survival analysis, age more than 50 years, tumor size that exceeded 3.9 cm, higher tumor grade, presence of marked vascular invasion, adjacent tissue invasion, and distant metastatic involvement at the time of initial diagnosis were associated with increased cancer mortality. Multivariate analysis (by Cox proportional hazards model), however, identified only age greater than 50 years, marked vascular invasion, and metastatic disease at the time of diagnosis to be independent predictors of follicular thyroid cancer-related mortality. Patients with two or more of these predictors were classified as being high risk. These patients had 5- and 20-year survival rates of 47% and 8%, respectively; the corresponding survival data for the low-risk group were 99% at 5 years and 86% at 20 years. The identification of these risk groups may facilitate a more rational approach to treatment of follicular thyroid cancer.

Left ventricular diastolic dysfunction presenting as ascites: the importance of clinically assessing central venous pressure. A 66-year-old man without history of heart disease or symptoms of left ventricular (LV) failure was admitted with transudative ascites. Echocardiography showed no valvular or pericardial disease and normal LV function. Gated pool scintigraphy confirmed normal LV systolic function but demonstrated severe right ventricular systolic dysfunction. Catheterization revealed left ventricular diastolic dysfunction as the cause of right-sided failure. The clinician evaluating transudative ascites cannot exclude LV failure on the basis of noninvasive assessment of systolic function alone. Appreciation of an elevated central venous pressure remains the most important evidence of a cardiac source of ascites.

Disseminated Pneumocystis carinii infection with hepatic involvement in a patient with the acquired immune deficiency syndrome. Extrapulmonary infection with Pneumocystis carinii (P. carinii) in AIDS patients is uncommon, and is often described only at postmortem examination. Although most antemortem cases involve spread to the bone marrow or spleen, P. carinii involvement of other organs has only recently been described. Despite the frequency of liver enzyme abnormalities in AIDS patients with a history of P. carinii pneumonia, P. carinii has been observed only rarely in the liver. We present a well-documented case of P. carinii involving the liver in an AIDS patient with P. carinii pneumonia and progressive liver enzyme abnormalities. We suggest that P. carinii infection should be considered in the differential diagnosis of AIDS-related liver disease.

Effects of discontinuation of phenytoin, carbamazepine, and valproate on concomitant antiepileptic medication. We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.

Reduction of post-traumatic swelling and compartment pressure by impulse compression of the foot. Following the discovery of a powerful venous pump in the foot that is activated by weight-bearing independently of muscular action, a pneumatic impulse device was developed to actuate this pump artificially. In a multicentre international trial the device was shown to reduce post-traumatic and postoperative swelling; pain also was alleviated. Evidence is also presented that dangerously high compartment pressures may be reduced to acceptable levels and fasciotomy avoided. We present an explanation of the clinical effects of activation of the venous footpump, based on recent improved understanding of the physiology of the microcirculation. The hyperaemic response that follows the liberation of endothelial-derived relaxing factor (EDRF) by sudden changes of pressure after weight-bearing or impulse compression is particularly important.

Cutaneous melanoma and bilateral retinoblastoma. We report the case of an otherwise healthy 37-year-old man who had had bilateral enucleation during early childhood for bilateral retinoblastomas, in addition to two cutaneous melanomas (the first appearing at age 27 years). He also had dysplastic melanocytic nevi and a history of cutaneous melanoma in his mother. Retinoblastoma may aggregate in families and is associated with DNA abnormalities of chromosome 13. Recent reports have emphasized the appearance of second malignancies in retinoblastoma survivors. The second malignancies include osteosarcoma, soft tissue sarcoma, and cutaneous melanoma. Cutaneous melanoma also may aggregate in families, usually in the setting of dysplastic melanocytic nevi. The features of this case and of similar reported cases suggest that there may be a greater than expected association between retinoblastoma and cutaneous melanoma.

Expression of pancreatic secretory trypsin inhibitor gene in human colorectal tumor. Expression of pancreatic secretory trypsin inhibitor (PSTI) gene was examined by Northern blotting analyses in 31 human colorectal tumors that included two benign adenomas and 26 adenocarcinomas. Among the total of 28 cases which proved to be adequate for mRNA analyses, all but one showed the expression of PSTI at various levels. In contrast, PSTI expression was not detected in two malignant lymphomas of the rectum. The level of PSTI expression was not correlated with the patient's age, sex, tumor location or size, stage of differentiation, lymph node metastasis, or progression stage. Some colorectal adenocarcinomas were also shown to express genes that can hybridize with human trypsinogen cDNA probe. It looks as though in these tumors, a protease(s) and its inhibitor are produced simultaneously as part of a cellular self-defense mechanism.

Spontaneous sump syndrome: Successful treatment by duodenoscopic sphincterotomy. "Sump syndrome" is a rare complication of side-to-side choledochoenterostomy operations which develops in the distal, nonfunctioning limb of the common bile duct where lithogenic bile, gastrointestinal contents, and debris accumulate. We report here a patient who developed spontaneous sump syndrome as a result of the formation of choledochoduodenal fistula, and who presented with multiple pyogenic liver abscesses. The patient's symptoms and liver abscesses resolved completely after treatment by endoscopic sphincterotomy and antibiotics. This case demonstrates that sump syndrome may occur spontaneously, that it can be a cause for pyogenic liver abscess formation, and that it may be treated effectively by endoscopic sphincterotomy.

A population-based study of functional status and social support networks of elderly patients newly diagnosed with cancer. We assessed the functional status and social support networks of 799 men and women aged 65 years or older newly diagnosed with cancer and living in six New Mexico counties. Functional limitations included depending on others for transportation (33%) and mental incompetence or poor recent memory (42%). The percentage of patients with functional limitation increased sharply with increasing age. In a substantial number of patients there was also evidence for poor social support networks; 26.5% of subjects lived alone and 38.9% had no children living in the vicinity. In a multiple logistic regression analysis, the predictors of having a poor social support network included non-Hispanic white ethnicity, advanced age, low income, and being a recent migrant to the area. Subjects with functional limitations were more likely to have poor social support networks than subjects without such limitations. The deleterious combination of impaired functional status and a limited social support network may explain why elderly cancer patients are at increased risk for not receiving appropriate therapy. Given the potential complexities involving the evaluation and appropriate treatment of cancer, care must be taken to adequately assess functional status and support mechanisms of older patients, and to provide adequate support to ensure compliance with treatment.

Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat. Severe arrhythmias occur predictably on reperfusion after 5 minutes of coronary occlusion in the rat. There is little data available on whether ischemic preconditioning (PC) of hearts can reduce the incidence of such arrhythmias. The effect of PC (three cycles of 2 minutes of coronary occlusion and 5 minutes of reperfusion) on development of arrhythmias after a subsequent 5-minute coronary artery occlusion and reperfusion was studied. Rats (n = 16 each group) underwent 5-minute occlusion and reperfusion alone or preceded by PC; arrhythmias were monitored during ischemia and for 10 minutes of reperfusion, and biopsies were taken for creatine phosphate and adenosine triphosphate in ischemic and nonischemic zones of the left ventricle. PC reduced the incidence of ventricular tachycardia (VT) during occlusion (81% control versus 13% PC, p less than 0.001). On subsequent reperfusion, ventricular fibrillation (VF) developed in zero PC animals versus 13 (81%) of controls (p less than 0.001), and irreversible VF in zero of PC versus seven (44%) of controls (p = 0.007). VT occurred in four (25%) of PC versus all (100%) of controls (p less than 0.001). PC reduced mean duration of VT plus VF from 320 +/- 54 to 5 +/- 1 seconds (p less than 0.001) and delayed arrhythmia onset from 8 +/- 2 to 85 +/- 35 seconds after reperfusion. There was no difference in creatine phosphate levels in the ischemic zone at the end of reperfusion in PC animals compared with controls without irreversible VF (16.2 +/- 4.1 versus 15.5 +/- 3.9 nmol/mg protein, p = NS).

Second cancer after radiation therapy for cancer of the uterine cervix. Radiation-induced cancers after radiation therapy for cancer of the uterine cervix were investigated on 11,855 patients including 5725 patients treated with radiation therapy alone, 1969 postoperative radiation therapy and 4161 surgery alone. The observed-to-expected ratios of the second primary cancer was 0.933 for the patients with radiation therapy alone and 1.074 for the patients with postoperative radiation therapy, respectively. No significant increase was observed in the risk of second primary cancers when all sites were combined. However, assessing on site by site basis, significant excess was noted for the rectum cancer, leukemia, and bladder cancer for the radiation therapy group but not for the surgery group. A significant excess of lung cancer was observed in both radiation therapy and surgery groups, which was attributed to some other causative factors. Radiation-induced cancers were suggested to develop apparently in organs involved in the irradiated field.

Phase II trial of piritrexim in metastatic melanoma using intermittent, low-dose administration. A phase II trial of piritrexim (2,4-diamino-6[2,5-dimethoxybenzyl]-5-methyl pyrido-[2,3d] pyrimidine, 301U74; PTX) was conducted for patients with metastatic malignant melanoma using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Thirty-one patients were entered onto the study. Among 31 patients assessable for response, there were two complete responses (CRs) and five partial responses (PRs) for a response rate (CR plus PR) of 23% (95% confidence limit, 10% to 42%). Five responses occurred in soft tissue lesions, and two responses occurred in lung lesions. The initial dose schedule was well tolerated. The dose-limiting toxicity was myelosuppression. PTX administered in this schedule appears to be active against malignant melanoma. Further clinical trials to confirm these results are underway.

Multiple-pulse stimulation and dantrolene in malignant hyperthermia. A potentially fatal condition, yet preventable, malignant hyperthermia (MH) lacks a satisfactory noninvasive diagnostic test. Studying the effects of intravenous dantrolene (3 mg/kg) on electrically stimulated skeletal muscle, we found that this approach does not conclusively distinguish between normal humans and those susceptible to malignant hyperthermia but nonetheless yielded important information about the action of dantrolene in man and in MH. Supramaximal single- and multiple-pulse stimulation of the common peroneal nerve produced stable torque responses of the dorsiflexor muscles (monitored in vivo), which dantrolene suppressed. With the multiple-pulse stimulation (5-6 pulses) this torque suppression was significantly less in MH-susceptible subjects than in control subjects. This distinction, also observed in MH swine, confirms this animal as a good model for human MH. That dantrolene's effect in MH can be more completely reversed with high frequency stimulation is intriguing; presumably, excitation-contraction coupling differs in MH and normal muscle.

Comparison of a 3- and 6-mm incision in combined phacoemulsification and trabeculectomy. We studied 216 eyes of 160 patients who underwent combined phacoemulsification and posterior chamber intraocular lens implantation with trabeculectomy. The mean follow-up was 18.7 months, with a minimum follow-up of six months. To assess the safety and efficacy of a recently developed 3-mm incision procedure with foldable intraocular lens implantation (phacotrabeculectomy), we compared 104 eyes subjected to this procedure with 112 eyes subjected to a 6-mm procedure at different follow-up periods. Intraocular pressure control (less than 21 mm Hg) was attained in 44 of 46 eyes (96%) in the 3-mm group and 71 of 76 eyes (93%) in the 6-mm group at one year postoperatively. Visual acuity of 20/40 or better was attained in 40 of 46 eyes (87%) in the 3-mm group and 66 of 76 eyes (87%) in the 6-mm group. The incidence of postoperative complication was significantly lower (P less than .001) and visual acuity in the early postoperative period was significantly better (P less than .01) in the 3-mm incision group than in the comparison group.

Evidence of a local immune activation in cystic brain tumors. The fluid of cystic brain tumors was characterized with regard to the protein content. In most malignant tumors, the concentrations of immunoglobulins G and M (IgG and IgM) were higher relative to other proteins in the cyst fluid than in the serum of the same patient. A markedly elevated ratio of monomeric to pentameric IgM was detected in the cyst fluid of two patients with glioblastomas. The results indicate a local immunoglobulin synthesis in malignant cystic brain tumors. It is hypothesized that higher-than-expected concentrations of IgG and IgM in cyst fluid as compared to plasma are a sign of an ongoing immune response triggered by the tumor.

Species-dependent effects of adenosine on heart rate and atrioventricular nodal conduction. Mechanism and physiological implications. This study 1) compares the negative chronotropic and dromotropic actions of adenosine in guinea pig, rat, and rabbit hearts; 2) investigates the mechanism(s) for the different responses; and 3) determines the physiological implications. Isolated perfused hearts were instrumented for measurement of atrial rate and atrioventricular (AV) nodal conduction time. Differences in metabolism of adenosine were determined in the absence and presence of dipyridamole (nucleoside uptake blocker) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, adenosine deaminase inhibitor). Dipyridamole plus EHNA decreased adenosine's EC50 for the negative dromotropic effect by 14-fold in guinea pig heart and 1.6-fold in rat heart. This is consistent with the greater number of [3H]nitrobenzylthioinosine binding sites measured in membranes from guinea pig (1,231 +/- 68 fmol/mg protein) compared with rat (302 +/- 31 fmol/mg protein) and rabbit (260 +/- 28 fmol/mg protein) atria. The potency of adenosine to slow atrial rate and prolong AV nodal conduction time was greater in guinea pig than in rat or rabbit hearts. This rank order of potency correlated well with the number of binding sites for the specific adenosine receptor radioligand 125I-aminobenzyladenosine in guinea pig (102 +/- 13 fmol/mg protein), rat (11 +/- 0.5 fmol/mg protein), and rabbit (8 +/- 1 fmol/mg protein) atrial membranes. Hypoxia increased the rate of adenosine release by severalfold and caused slowing of heart rate and AV block. In spontaneously beating hearts, the main effect of hypoxia was a slowing of ventricular rate, which in the guinea pig heart was due to AV block and in the rat heart to atrial slowing. In atrial paced hearts, hypoxia caused a marked prolongation of AV nodal conduction time in guinea pig (39 +/- 4 msec) and rabbit (29 +/- 5 msec) hearts, but only small effect in rat hearts (10 +/- 2 msec). The differences in response to hypoxia could be accounted for by the species-dependent differences in the 1) amount of adenosine released and metabolized, 2) sensitivity of the hearts to adenosine, and 3) dependency of AV nodal conduction on atrial rate. The findings indicate that the results from physiological or pharmacological studies on adenosine in one species may not be applicable to others, and the ultimate effect of adenosine and hypoxia is to slow ventricular rate.

Critical review of gangliosides and thyrotropin-releasing hormone in peripheral neuromuscular diseases. The lack of effective therapy for many of the chronic neuromuscular diseases such as amyotrophic lateral sclerosis, hereditary motor sensory neuropathy (Charcot-Marie-Tooth disease), spinocerebellar degenerations and idiopathic polyneuropathy has led to a search for substances that may stimulate peripheral nerve regeneration. Two such agents that have been proposed are gangliosides (mixed purified bovine brain gangliosides, Cronassial) and thyrotropin releasing factor (TRH). Studies on both of these agents were initially reported with enthusiasm to be successful, but later double-blind controlled studies have failed to confirm these findings. This review provides critical analysis of the designs of studies of potentially effective agents in chronic neuromuscular diseases, and emphasizes the power of the placebo response, and the importance of designing placebos which are indistinguishable from the trial medication other than in the active effect.

Is routine preoperative hemodynamic evaluation of nonagenarians necessary? An Incidence of co-morbid cardiac disease in the elderly surgical patient as high as 66% has been previously reported. Even in the absence of clinically significant cardiac disease, advanced age alone is often considered sufficient indication for Swan-Ganz placement, hemodynamic evaluation, adjustment of fluid states, and inotropic support. Yet data clearly documenting the need for this evaluation and therapy are difficult to obtain. All major general surgical and orthopedic operations in non-agenarians were reviewed in our institution from July 1, 1987 through December 31, 1988. Fifty-one procedures were performed on 46 patients. None of these patients had preoperative Swan-Ganz catheterization or hemodynamic evaluation. Eighteen general surgical, 30 orthopedic, 2 neurosurgical, and 1 gynecological procedures were performed. Forty-three were performed under general anesthesia, 7 under spinal anesthesia, and 1 with local anesthesia. Seven out of 51 patients (14%) experienced major complications, and 16 out of 51 (31%) experienced minor complications. Thirty-day mortality was 0%, and 6-month survival was 92%. Only one complication occurred within 48 hours of surgery that might possibly have been prevented with hemodynamic evaluation, adjustment of fluid status, inotropic support, and intensive care unit monitoring.

Prospective study of a prosthetic H-graft portacaval shunt. This study was undertaken to prospectively evaluate the 8-mm Gore-Tex interposition H-graft portacaval shunt. Thirty-six high-risk patients at the University of South Florida-affiliated hospitals received small-diameter shunts because of bleeding esophagogastric varices over a recent 2-year period. Portal vein and portal vein-inferior vena cava gradients were significantly reduced after shunting. These pressure changes were manifested clinically by the absence of variceal rebleeding and improvement of ascites; in addition, the incidence of encephalopathy was low. The 8-mm graft maintained hepatopedal flow in 67% of the patients, but reversal of flow did not result in complications commonly associated with poor portal perfusion. Graft thrombosis occurred in four (11%) patients. All grafts were successfully revised, three by operative revision and one by an interventional radiologist. Operative mortality was low (11%), and morbidity was unusual. The small-diameter H-graft portacaval shunt is a safe and effective method of treatment for bleeding esophagogastric varices.

Unusual lymphoproliferative oropharyngeal lesions in heart and heart-lung transplant recipients. Three unusual cases of oropharyngeal lympho-proliferative lesions were seen in recipients of heart and heart-lung transplants. Two caused acute upper respiratory obstruction necessitating urgent ENT intervention. All patients were receiving immunosuppressive drugs including cyclosporin. The two obstructive cases were adenotonsillar enlargement in a 6-year-old, and a tumour of the tonsil and tongue base with cervical lymph node enlargement in a 32-year-old male. Both were caused by Epstein-Barr Virus-associated lymphoproliferative disorder. The third patient, a 32-year-old female, had a presumed low grade T-cell lymphoma that regressed spontaneously. Histopathological diagnosis of these lympho-proliferative disorders after transplantation usually requires immunocytochemistry to distinguish polyclonal proliferative disorders from true lymphoma. Polyclonal lymphoproliferative disorders after transplantation do not usually require aggressive cytoreductive therapy, but respond to simple measures such as the reduction of immunosuppression.

Peripheral arterial occlusive disease: prospective comparison of MR angiography and color duplex US with conventional angiography. Conventional angiography, two-dimensional inflow magnetic resonance (MR) angiography, and color duplex ultrasound (US) were performed on 12 patients in a blinded, prospective study. The ability to grade arterial lesions and plan revascularization interventions were compared. Arterial lesions were categorized as nonsignificant (0%-49% diameter reduction) or significant (50%-100% diameter reduction). Determination of nonsignificant and significant lesions with MR angiography was in agreement with that at conventional angiography in 100 of 140 lesions (71%). Agreement between results of conventional angiography and color duplex US occurred with 114 of 123 infrainguinal lesions (93%). Twenty-one vascular interventions were planned by using conventional angiography; there was agreement with color duplex US in 11 cases and MR angiography in five. Color duplex US performed well in the assessment of infrainguinal disease but was limited in the evaluation of iliac segments because of nonvisualization. The iliac region was visualized in more patients with MR angiography than with color duplex US, but image quality with MR angiography was inconsistent. Strategies to improve MR angiography of the peripheral vasculature merit further study.

Preventing postoperative acute bleeding of the upper part of the gastrointestinal tract. Two hundred and ninety-eight critically ill patients at risk for the development of postoperative stress ulcers and bleeding were randomized into three groups. The first group comprised 85 patients who received meciadanol, a new bioflavonoid, 500 milligrams every six hours through a nasograstric tube; the second group comprised 100 patients who received sucralfate (crushed tablets), 1,000 milligrams every six hours through a nasogastric tube, and the third group comprised 113 patients who received an antacid (Maalox [magnesium aluminum hydroxide gel]) through a nasogastric tube at an initial dose of 15 milliliters every hour. The gastric pH was measured hourly and titrated to a pH greater than or equal to 4.0 in patients in the group receiving the antacid. The gastric pH was measured every two hours in the other two groups. Bleeding in the upper part of the gastrointestinal tract was determined visually (frank blood in gastric contents) or by guaiac testing. Bleeding occurred in seven patients receiving meciadanol, nine receiving sucralfate and six receiving the antacid. The difference in rates of bleeding was not statistically significant. Correlation between the severity of illness index and the development of bleeding was poor, at least in the low and intermediate index range. In contrast, there was a strong correlation between the age of the patient and the development of bleeding. Only one patient younger than 50 years had bleeding develop. Apparently, meciadanol exerts its action by a mechanism other than pH control. It may, therefore, fill an important gap in the ability to prevent postoperative stress ulcers and bleeding.

Residual atrial septal perforation after percutaneous transvenous mitral commissurotomy with Inoue balloon catheter. To estimate the incidence of residual atrial septal perforation (ASP) following percutaneous transvenous mitral commissurotomy (PTMC) with the Inoue balloon catheter and to examine the factors contributing to ASP, we studied 46 patients with mitral stenosis undergoing PTMC. Residual ASP was evaluated by Doppler color flow imaging 1 day after PTMC, and was detected in 7 out of 46 patients (15.2%). We examined the relationship between the development of ASP (ASP+) and the age of the patient, the left atrial dimension before PTMC, the mean pressure difference between left and right atrium after PTMC, and the duration of the procedure from atrial septal puncture by the Brockenbrough method to balloon inflation. There was a good correlation between the development of residual ASP and the duration of the procedure (ASP+, 51.0 +/- 34.0 minutes; without ASP, 24.6 +/- 16.2 minutes; p less than 0.01). However, there was no significant correlation between the development of ASP and other factors. In the follow-up study, ASP disappeared in four patients within 3 months. ASP persisted in two patients for 1 year after PTMC. However, the shunt in these two patients was clinically insignificant. These data suggest that residual ASP may depend on the duration of the procedure, and that most cases of ASP disappear within 1 year after PTMC.

Childhood traumas: an outline and overview Childhood psychic trauma appears to be a crucial etiological factor in the development of a number of serious disorders both in childhood and in adulthood. Like childhood rheumatic fever, psychic trauma sets a number of different problems into motion, any of which may lead to a definable mental condition. The author suggests four characteristics related to childhood trauma that appear to last for long periods of life, no matter what diagnosis the patient eventually receives. These are visualized or otherwise repeatedly perceived memories of the traumatic event, repetitive behaviors, trauma-specific fears, and changed attitudes about people, life, and the future. She divides childhood trauma into two basic types and defines the findings that can be used to characterize each of these types. Type I trauma includes full, detailed memories, "omens," and misperceptions. Type II trauma includes denial and numbing, self-hypnosis and dissociation, and rage. Crossover conditions often occur after sudden, shocking deaths or accidents that leave children handicapped. In these instances, characteristics of both type I and type II childhood traumas exist side by side. There may be considerable sadness. Each finding of childhood trauma discussed by the author is illustrated with one or two case examples.

Outcome of CPR in a large metropolitan area--where are the survivors? STUDY OBJECTIVES: Survival from out-of-hospital cardiac arrest in cities with populations of more than 1 million has not been studied adequately. This study was undertaken to determine the overall survival rate for Chicago and the effect of previously reported variables on survival, and to compare the observed survival rates with those previously reported. DESIGN: Consecutive prehospital arrest patients were studied prospectively during 1987. SETTING: The study area was the city of Chicago, which has more than 3 million inhabitants in 228 square miles. The emergency medical services system, with 55 around-the-clock ambulances and 550 paramedics, is single-tiered and responds to more than 200,000 emergencies per year. TYPE OF PARTICIPANTS: We studied 3,221 victims of out-of-hospital cardiac arrest on whom paramedics attempted resuscitation. MEASUREMENTS AND MAIN RESULTS: Ninety-one percent of patients were pronounced dead in emergency departments, 7% died in hospitals, and 2% survived to hospital discharge. Survival was significantly greater with bystander-witnessed arrest, bystander-initiated CPR, paramedic-witnessed arrest, initial rhythm of ventricular fibrillation, and shorter treatment intervals. CONCLUSIONS: The overall survival rates were significantly lower than those reported in most previous studies, all based on smaller communities; they were consistent with the rates reported in the one comparable study of a large city. The single factor that most likely contributed to the poor overall survival was the relatively long interval between collapse and defibrillation. Logistical, demographic, and other special characteristics of large cities may have affected the rates. To improve treatment of cardiac arrest in large cities and maximize the use of community resources, we recommend further study of comparable metropolitan areas using standardized terms and methodology. Detailed analysis of each component of the emergency medical services systems will aid in making improvements to maximize survival of out-of-hospital cardiac arrest.

Syndromes of transient amnesia: towards a classification. A study of 153 cases. Of 153 patients presenting with acute transient amnesia, 114 fulfilled the proposed strict diagnostic criteria for transient global amnesia (TGA). The prognosis of this group was excellent with the exception of a small subgroup (7%), largely identifiable because of atypically brief or recurrent attacks, who developed epilepsy of temporal lobe type on follow up. Computerised tomography (CT) scans performed on 95 patients were normal, evidence for covert alcoholism was lacking and there was a familial incidence of approximately 2%. By contrast, the group of 39 patients who did not meet the criteria for TGA had a significantly worse prognosis with a high incidence of major vascular events. The groups could not be distinguished on the basis of behavioural characteristics during the attack. The following classification was proposed: 1) pure TGA--attacks fulfilling the strict criteria, and of more than one hour in duration which do not require detailed investigation, 2) probable epileptic amnesia--attacks of less than an hour or rapidly recurrent, 3) probable transient ischaemic amnesia, a minority of cases with additional focal neurological deficits during the attack.

A comparison in vitro of human and rabbit distal colonic muscle responses to inflammatory mediators. The present study compared in vitro the motor responses of human and rabbit distal colonic longitudinal and circular muscle to acetylcholine, histamine, leukotrienes B4 and D4, and prostaglandins E2 and F2 alpha. The active and passive mechanical properties of these muscles were also evaluated. All muscle types were contracted by acetylcholine and histamine. Longitudinal muscle from both species was contracted by prostaglandin E2 and prostaglandin F2 alpha, although rabbit muscle was more sensitive. Prostaglandin E2 relaxed the majority of both human and rabbit circular muscle preparations that were studied. Prostaglandin F2 alpha first relaxed and then contracted circular muscle from both species. Leukotriene B4 had no effect on any tissue studied. Leukotriene D4 caused transient relaxations in a proportion of all muscle types, but the relaxations were not concentration-related. Contractile responses did not differ under isotonic recording conditions, but relaxations were much more clearly defined. Based on experiments using atropine, phentolamine and propranolol, and pyrilamine or tetrodotoxin, it was concluded that the responses of both human and rabbit distal colonic muscles to these inflammatory mediators have a similar pharmacological basis. All muscle types exhibited low passive tension and developed active tension in the range 0.8-1.2 Lo. These data strongly support the belief that after the onset of an induced colitis, the rabbit colon has value as a predictive model for the study of inflammatory mediator-induced colonic motility changes in humans.

Early cerebral infarction: gadopentetate dimeglumine enhancement Gadopentetate dimeglumine was administered prospectively to 50 patients who presented for magnetic resonance (MR) imaging within 2 weeks after a cortical cerebral infarction. Twenty-two patients (44%) were imaged within 3 days after clinical ictus. Abnormalities detected with gadopentetate dimeglumine enhancement were observed in 46 (92%) of 50 patients. Classic parenchymal enhancement was a late finding, observed in all patients (17 of 17) imaged at 7-14 days after infarction. Before this time, three additional phases of contrast material-related abnormalities were observed. Enhancement of vessels supplying the infarct ("intravascular enhancement sign") was the earliest finding, seen in 17 (77%) of 22 infarcts aged 1-3 days. From day 2 to day 6, abnormal enhancement of meninges adjacent to the infarct was frequently noted ("meningeal enhancement sign"). Finally, a transition phase that combined intravascular or meningeal enhancement with early parenchymal enhancement was seen from day 3 to day 6. Gadopentetate dimeglumine-enhanced MR imaging in early stroke reveals evidence of vascular engorgement and sluggish flow, which precede the development of classic parenchymal enhancement.

Stroke rehabilitation: Australian patient profile and functional outcome. A prospective, multi-institutional, population based study identified 1274 non-surgical stroke admissions to all hospitals in a major Australian city during 1984. The demographic and diagnostic profile and the nature of functional recovery of all 258 first stroke survivors who were referred for inpatient rehabilitation are presented. The median duration of rehabilitation stay was 49 days. The mean functional independence score, as measured on a modified Barthel Index at admission was 44, compared with 78 on discharge, a mean improvement of 34. Stair climbing had the lowest mean value on admission (12), while bowel control had the lowest residual deficit on discharge (95). The stroke study group was representative of the unimpaired aged population in all respects except ethnicity, where differences are attributed to age. The variables identified as significant are; side and severity of paralysis, age and sex, marital status and ethnicity. Stroke rehabilitation outcome was not influenced by etiology, site of lesion, arterial distribution, occupation or education.

Neural respiratory drive and neuromuscular coupling in patients with chronic obstructive pulmonary disease (COPD). In 15 spontaneously breathing patients with chronic obstructive pulmonary disease (COPD) divided into two groups, one with normocapnia (A) and one with chronic hypercapnia (B), we evaluated the maximal voluntary inspiratory muscle strength (MIP), the pattern of breathing, the mouth occlusion pressure (Po.1), the neural respiratory drive (NRD), assessed by surface electromyographic (EMG) activity of the diaphragm (EMGd) and EMG activity of intercostal muscles (EMGint), and the chest wall neuromuscular coupling, assessed in terms of Po.1/EMGd ratio. Compared with an age-matched normal control group, both A and B groups exhibited lower MIP, significantly greater EMGd and EMGint, and lower Po.1/EMGd ratio. However, a similar pattern, along with a rapid and shallow breathing, differentiated group B from group A. In group B we found a significant direct relationship between Po.1/EMGd ratio and MIP, and an inverse relationship between PaCO2 and Po.1/EMGd ratio. These data seem to indicate the following: (1) EMG is a more precise method than Po.1 in assessing the magnitude of the NRD; (2) NRD is increased in these patients; and (3) clinical manifestations probably associated with inspiratory muscle fatigue (marked decrease in muscle strength, rapid and shallow breathing, and alveolar hypoventilation) may be accompanied by a greater NRD and a more marked derangement in chest wall neuromuscular coupling in COPD.

Freehand allograft aortic valve replacement and aortic root replacement. Utility of intraoperative echocardiography and Doppler color flow mapping. Seventeen consecutive patients undergoing 20 planned aortic valve replacements with allograft valves at Stanford University Medical Center were studied with intraoperative epicardial echocardiography and Doppler color flow mapping before and after cardiopulmonary bypass. Native aortic valves were replaced in 12 of the 20 patients, and eight patients underwent second aortic valve procedures. In 17 of 20 patients allograft selection was guided by prebypass echocardiographic estimates of annular diameter and/or length of allograft aortic root required. Other prebypass findings included unanticipated severe mitral regurgitation in one patient (which precluded allograft aortic valve replacement), left-to-right shunts in five patients, ascending aortic dissection in one, and aortic root disease necessitating coronary reimplantation or bypass in two. Postbypass echocardiography demonstrated acceptable competency of 18 of 19 allograft valves (mild or no aortic insufficiency). Postbypass echocardiography also documented successful repair of four of five shunts and mild mitral regurgitation in 15 of 19 patients (versus 11 of 19 before bypass). Conclusions: Intraoperative echocardiography-Doppler mapping is a useful adjunct for allograft aortic valve or aortic root replacement; it allows confident selection of appropriate tissue size before aortic cross clamping, which minimizes delay from allograft thawing procedures. It also provides helpful information about the extent of aortic root disease and coronary ostial anatomy before bypass, confirms allograft competency after bypass, and detects accompanying valvular and other hemodynamic lesions before and after allograft valve replacement.

A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells. Malignant spreading of cancer cells requires cell surface proteases that cleave the crosslinked collagenous matrix of connective tissues. From correlating the morphologically defined invasiveness of tumor cells with the presence of specific membrane-associated proteases, we have identified a malignant human melanoma cell line, LOX, that invades crosslinked gelatin films in vitro and contains uniquely a neutral 170-kDa gelatinase in the cell membrane. A similar gelatinase was found in membranes recovered from culture media conditioned with LOX. The 170-kDa gelatinase is a wheat germ agglutinin-binding protein. The proteolytic activity is maximal at neutral pH, enhanced by EDTA and dithiothreitol, inhibited by the cysteine protease inhibitors N-ethylmaleimide, HgCl2, and phenylmethylsulfonyl fluoride, and can bind to an organomercurial adsorbent, suggesting that it is a neutral sulfhydryl-sensitive protease. This 170-kDa gelatinase of LOX cells was not found in a control melanoma cell line, SK-MEL28, or in 32 other tumor cell lines that did not show extracellular gelatin degradation. Thus, we have identified a large membrane-bound protease that may be a specific marker molecule for melanoma cell invasiveness.

Ablation of the atrioventricular junction with radiofrequency energy using a new electrode catheter. Percutaneous catheter ablation using radiofrequency energy can be used to interrupt atrioventricular (AV) conduction in patients with supraventricular tachycardia refractory to drugs. Results of radiofrequency ablation of the AV junction using a custom-designed catheter with a large, 3-mm-long distal electrode, 2-mm interelectrode spacing, and a shaft with increased torsional rigidity were compared with those using a standard quadripolar electrode catheter (Bard EP). An electrocoagulator (Microvasive Bicap 4005) supplied unmodulated radiofrequency current at 550 kHz, which was applied between the distal electrode of the ablation catheter and a large skin electrode. With use of the modified catheter, 12 of 13 patients (92%) had persistent complete AV block induced with 7 +/- 5 applications of 18 +/- 6 W of radiofrequency power. In contrast, complete AV block was produced in only 9 of 18 (50%) historical control patients treated with the standard catheter, despite a similar number of applications (7 +/- 5) and power output (16 +/- 4 W). A rise in impedance, due to desiccation of tissue and coagulum formation, occurred earlier (28 +/- 18 vs 52 +/- 24 seconds, p less than 0.001) and more frequently (54 vs 40% of applications, p = 0.047) in patients treated with the standard catheter than in patients treated with the modified catheter. The use of a catheter designed to increase the surface area of electrode-tissue contact allows more radiofrequency energy to be delivered before a rise in impedance occurs and appears to increase the effectiveness of radiofrequency ablation of the AV junction.

Immunohistologic properties of benign and malignant mixed tumor of the lacrimal gland. We studied the immunohistopathologic features of normal lacrimal gland, benign mixed tumor, and malignant mixed tumor of the lacrimal gland. Primary antisera were to keratin, muscle-specific actin, vimentin, and glial fibrillary acid protein. Keratin stained in occasional myoepithelial cells in normal gland, ductal epithelium in normal gland and the tumors, and occasional stromal epithelioid cells in the tumors. Muscle-specific actin stained in myoepithelium and vascular smooth muscle in normal gland and the tumors, and occasional spindle-shaped and clusters of stromal cells in the tumors. Vimentin staining was nonspecific. Glial fibrillary acid protein stained in occasional myoepithelial cells in normal gland and polyhedral stromal cells in benign mixed tumor. Our findings indicate that ductal epithelium develops into the epithelial component, and some cells in the stroma and myoepithelium develop into some cells in the stroma of benign and malignant mixed tumor of the lacrimal gland.

A double-blind comparative study of doxazosin and prazosin when administered with beta-blockers or diuretics. The antihypertensive efficacy and safety of doxazosin (once daily) and prazosin (twice daily) were compared in patients with mild or moderate essential hypertension (diastolic blood pressure [DBP] 95 to 114 mm Hg) not adequately controlled by diuretics and beta-blockers. Doxazosin produced significantly greater mean reductions in standing (p = 0.01) and supine (p = 0.04) DBP than did prazosin; there were no significant between-group differences in either mean systolic blood pressure or heart rate. The overall mean daily doses for efficacy-evaluable patients were 4.7 mg of doxazosin and 6.7 mg of prazosin. Sixteen patients (84.2%) treated with doxazosin and 13 patients (56.5%) treated with prazosin were considered therapeutic successes (decrease in standing DBP greater than or equal to 10 mm Hg or to less than or equal to 90 mm Hg with greater than or equal to 5 mm Hg reduction from baseline). Of the 19 efficacy-evaluable patients treated with doxazosin, 15 (78.9%) showed improvement in the severity category of hypertension; an improvement in severity was reported in 14 patients (60.9%) treated with prazosin. Doxazosin produced a more favorable effect on serum lipid levels than did prazosin, although no statistically significant within- or between-group differences were observed. Most side effects experienced with either doxazosin or prazosin were mild or moderate and were tolerated or disappeared with continued treatment. The overall evaluation of toleration was excellent or good for 18 (90%) doxazosin- and 21 (91%) prazosin-treated patients. Clinical efficacy was rated as excellent or good for 16 patients (80%) treated with doxazosin and 15 patients (68%) treated with prazosin.

Operative findings after percutaneous pulmonary balloon dilatation of the right ventricular outflow tract in tetralogy of Fallot. Since 1983 percutaneous balloon dilatation of the right ventricular outflow tract has been performed as an alternative to surgical palliation in selected cases of tetralogy of Fallot at the Royal Liverpool Children's Hospital. From 31 December 1984 to 31 December 1988, 27 of these patients underwent subsequent surgical correction. Age at operation ranged from 7 to 58 months (median 2.7 years). The mean interval between balloon dilatation and correction was 15.6 months (range 3-39 months). Two patients had a systemic pulmonary shunt operation performed before dilatation and a further five required one afterwards. Overall 20 (74%) patients had some anatomical alteration as the result of balloon dilatation, while in seven (26%) there was no discernible change in the right ventricular outflow tract. There was no consistent relation between the ratio of balloon size to pulmonary annulus diameter and the morphological findings. Balloon dilatation may obviate the need for systemic-pulmonary shunt at the expense of some structural damage, particularly to the posterior cusp. The present data suggest that dilatation does not bring about growth of the annulus to such an extent that transannular patch is no longer needed at intracardiac repair.

Neuroendocrine design of the gut. The enteric nervous system (ENS) can be thought of as the third component of the autonomic nervous system. It is a vast network of neurons widely dispersed throughout the gut. The ENS is a dominant regulator of gut function through the action of peptide and non-peptide neurotransmitters. The most intensively studied roles of the ENS have been the regulation of secretory processes, such as gastric acid secretion, and motility. It is clear, however, that the ENS plays a broader role in the regulation of other gut functions, including mucosal defense, the gut immune response, and sphincter function. Alterations in the regulation of gut function by the ENS are likely or suspected in a number of conditions, including achalasia, Hirschsprung's disease, inflammatory bowel disease, Chagas' disease, chronic intestinal pseudoobstruction, biliary dyskinesia, tachygastria, and irritable bowel syndrome. Improved knowledge of the pathophysiology of these troublesome conditions makes effective therapy more likely in the future.

Aneurysmal dilatation in saphenous vein bypass grafts. Three patients are reported who developed aneurysmal degeneration of a saphenous vein arterial bypass graft. All three had hypercholesterolemia and two had marked elevation of triglycerides. One bypass was for occlusive disease and two for popliteal aneurysm. There was a long lag, 3 to 7 years between graft implantation and aneurysmal degeneration. The pathology was similar for all three cases with lipid laden macrophages, loss of elastic lamina, and other atherosclerotic changes in the vein wall. While atheromatous changes and aneurysm formation in saphenous vein bypass grafts are rare, this may occur especially in patients with hypercholesterolemia and hypertriglyceridemia. Careful and prolonged follow-up plus vigorous management of the hyperlipidemic state is mandatory in these patients.

Results of primary angioplasty for acute myocardial infarction in patients with multivessel coronary artery disease. The influence of multivessel coronary artery disease on the outcome of reperfusion therapy for myocardial infarction has not been fully characterized. Direct coronary angioplasty without antecedent thrombolytic therapy was performed during evolving myocardial infarction in 285 patients with multivessel coronary artery disease at 5.2 +/- 4.2 h after the onset of chest pain. Two vessel disease was present in 163 patients (57%) and three vessel disease in 122 (43%). An anterior infarct was present in 123 patients (43%), cardiogenic shock in 33 (12%) and age greater than or equal to 70 years in 59 (21%). Angioplasty of the infarct-related vessel was successful in 256 patients (90%), including 92% with two vessel and 88% with three vessel disease (p = NS). Emergency bypass surgery was needed in six patients (2%). In-hospital death occurred in 33 patients (12%), including 13 with two vessel and 20 with three vessel disease (p less than 0.05). The mortality rate was only 4% in the subgroup of 101 patients who met entry criteria for thrombolytic trials. The in-hospital mortality rate was 45% in patients in shock and 7% in patients not in shock (p less than 0.01). Logistic regression analysis identified shock and age greater than or equal to 70 years as independently associated with in-hospital death. In 135 patients who underwent predischarge left ventriculography, global ejection fraction increased from 50% to 57% (p less than 0.001) and regional wall motion in the infarct zone improved in 59% of patients. Follow-up data were available in 251 patients (99%) at a mean of 35 +/- 19 months.

Orchiectomy versus oestrogen in the treatment of advanced prostatic cancer. The primary clinical efficacy of orchiectomy and the combination therapy of intramuscular polyoestradiol phosphate 80 mg monthly and oral ethinyl oestradiol 0.15 mg daily was evaluated by progression and cancer mortality rates in a series of 277 prostatic cancer patients representing part of the Finnprostate study. After a follow-up of 5 years there was a significant difference between the groups in terms of progression rate and prostatic cancer deaths. The oestrogen combination was more effective in delaying progression of the disease. The overall mortality rate was similar in both groups. About one-third of the patients were alive after 5 years.

Partial cytochrome b deficiency and generalized dystonia. An 18-year-old female had clinical features of idiopathic torsion dystonia with bilateral hypodense putaminal lesions on computed tomography. Mitochondrial encephalomyopathy was suspected because of persistent lactic acidemia and myopathy. Studies of oxidative metabolism on isolated skeletal muscle mitochondria revealed partial cytochrome b deficiency indicating a defect in the cytochrome b- c1 complex. This finding represents a unique, multisystem syndrome of progressive dystonia, putaminal degeneration, myopathy, and mitochondrial cytochrome b deficiency. Mitochondrial metabolic disorders may be a cause of torsion dystonia when other known associated factors are absent.

Quinine-induced disseminated intravascular coagulation. Recurrent disseminated intravascular coagulation occurred in 3 women after ingestion of quinine tablets for cramp. All had circulating quinine-dependent antibodies to platelets and in 2 there was initial evidence of antibody consumption, with low titres that rose steeply over the next few days and remained high for many months.

The frequency of uterine leiomyomas. As a leading cause of hysterectomy in premenopausal women. uterine leiomyomas are a major public health problem. However, very little work has been done on their epidemiology. Indeed, their true frequency has never been established using systematic and meticulous methods. In this study, gross serial sectioning at 2-mm intervals was applied as an adjunct to routine pathology processing in 100 consecutive total hysterectomy specimens. This tripled the number of leiomyomas noted in routine pathology reports. There were 649 leiomyomas in 77 of 100 uteri, with multiplicity of leiomyomas in 84%. Although leiomyomas were more numerous and larger in women with a clinical diagnosis of myomatous uterus, the incidence was no higher than in uteri removed for other reasons. The postmenopausal incidence of leiomyomas was no lower than the premenopausal incidence, although postmenopausal leiomyomas were smaller and fewer. These findings suggest that epidemiologic studies of leiomyomas may not be valid if they are based only on clinical diagnoses or routine pathology reports.

Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain. This report examines the relationship of plasma drug concentration to analgesic effect following bolus doses of alfentanil, fentanyl and morphine and assesses individual differences in analgesic response among volunteers. We predicted that the 3 opioids would yield disparate analgesic profiles because their physicochemical and pharmacokinetic characteristics differ. Ten healthy volunteers received intravenous bolus doses of either alfentanil, fentanyl, morphine or normal saline on different days. We stimulated their teeth electrically and measured brain evoked potential (EP) and pain report (PR) repeatedly over 2 h to assess analgesic effect. Concurrently, we drew 18 blood samples to assess opioid plasma concentrations during the test period. The relationship between opioid plasma concentration and analgesic effect was well defined for alfentanil but ambiguous for morphine. Fentanyl exhibited a marked hysteresis. We observed noteworthy individual differences in analgesic response with all 3 drugs but these differences were greatest for morphine and least for alfentanil. Inter- and intrasubject variability in analgesic response across drugs is related to the physicochemical properties of the drugs tested.

Clinical efficacy of flosequinan in heart failure. The effects of the new arterial and venous vasodilator flosequinan have been evaluated in a variety of ways in different groups of patients with chronic heart failure. Flosequinan improved the central hemodynamic effects of heart failure in one group, with benefits still apparent up to 24 hours after a single oral dose. In another group it also improved calf blood flow and, therefore, blood flow to skeletal muscle. Also, using a number of different tests, it improved the exercise performance of the patients. In a further group the improvement in exercise tolerance produced was similar to that of captopril. Flosequinan has the necessary properties of a drug that is likely to be of benefit in the treatment of patients with chronic heart failure.

Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status. Breast tumor cell lines have been shown to secrete several distinct polypeptide growth factors, although conflicting results exist for the insulin-like growth factors (IGFs). In contrast a limited number of breast tumor cell lines have definitely been shown to secrete the high affinity IGF binding proteins (IGFBPs) that modify IGF actions. To characterize the types of IGFBPs that are secreted by breast tumor cell lines, conditioned medium was collected from seven separate tumor cell lines, three of which were estrogen receptor (ER) negative, and four of which were ER positive. All three of the ER negative cell lines, MDA-231, MDA-330, and HS578T, secreted binding proteins of 49,000 and 43,000 Mr (IGFBP-3) as well as 29,000 (IGFBP-1) and 24,000 Mr. In contrast, all four ER positive cell lines secreted 34,000 (IGFBP-2) or 24,000 Mr forms, and none secreted the 49,000 and 43,000 or 29,000 Mr forms. BT-20, a cell line that is positive for ER messenger RNA (mRNA) but negative for ER protein, secreted predominantly a 34,000 Mr protein. The amount of total IGFBP activity released in 24 h ranged between 0.4 and 5.6 nM equivalents of IGFBP-1, and there was no significant difference between the ER positive and negative cell lines. The MCF-7 cells that produced predominantly 34,000 and 24,000 Mr forms showed a 1.8-fold increase in IGFBP secretion after estrogen stimulation. Immunoblotting and a specific RIA for IGFBP-1 showed that only the ER negative lines MDA-330, MDA-231, and HS578T secreted this form. Northern blotting analysis for the mRNA encoding this protein showed that both MDA-330 and MDA-231 contained a single 1.6 kilobase mRNA species that hybridized with an IGFBP-1 complementary DNA (cDNA) probe. Immunoblotting analysis of the other cell lines showed that only the 34,000 Mr form secreted by the ER positive cell lines reacted with IGFBP-2 antisera. Exposure of the conditioned media from the three ER negative cell lines to N-glycanase revealed that the 49,000 and 43,000 Mr forms of IGFBP were glycosylated and therefore probably represent IGFBP-3. We conclude that ER negative cell lines secrete three forms of IGFBPs, IGFBP-1, IGFBP-3, and a 24,000 Mr form. In contrast, the ER positive cell lines secrete predominantly IGFBP-2 and the 24,000 Mr form but do not secrete IGFBP-3 or 1.(ABSTRACT TRUNCATED AT 400 WORDS).

Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms. Neurohormonal factors were investigated in 10 patients with functional dyspepsia who had normal or slow upper gut transit and 10 age- and sex-matched healthy controls. Gastric and small bowel motility and transit, jejunal responses to luminal distention and IM neostigmine, gut hormones, and vagal and sympathetic functions were studied. Slow upper gut transit was defined by a gastric emptying slope less than 0.3%/min or 10% small bowel transit time greater than 300 minutes. Four patients with slow transit had reduced postprandial antral motility and gut hormone responses. Two of the four patients had vagal and sympathetic dysfunction. In 6 patients with normal transit, balloon distention in the jejunum was perceived at a lower volume (32.7 +/- 5.9 mL) than in controls (46.6 +/- 3.0 mL). Pressure responses to balloon distention were reduced in 5 and exaggerated in 1 patient; abnormal efferent vagal (2 patients) and sympathetic (1 patient) function were also documented. In view of the normal transit, motility, and jejunal pressure responses to neostigmine in all 6 patients, the abnormal response to distention suggests afferent dysfunction. Functional dyspepsia is a heterogenous disorder. Abnormal transit is sometimes associated with disorders of extrinsic neural control, but the latter are also found in patients with normal transit. Increased perception of intraluminal stimuli in those with normal transit suggests a disturbance in afferent function.

Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. Systemic administration of the cytokine, TGF beta 1, profoundly antagonized the development of polyarthritis in susceptible rats. TGF beta 1 administration (1 or 5 micrograms/animal), initiated one day before an arthritogenic dose of streptococcal cell wall (SCW) fragments, virtually eliminated the joint swelling and distortion typically observed during both the acute phase (articular index, AI = 2.5 vs. 11; P less than 0.025) and the chronic phase (AI = 0 vs. 12.5) of the disease. Moreover, TGF beta 1 suppressed the evolution of arthritis even when administration was begun after the acute phase of the disease. Histopathological examination of the joint revealed the systemic TGF beta 1 treatment greatly reduced inflammatory cell infiltration, pannus formation, and joint erosion. Consistent with the inhibition of inflammatory cell recruitment into the synovium, TGF beta 1 reversed the leukocytosis associated with the chronic phase of the arthritis. Control animals subjected to the same TGF beta 1 dosing regimen displayed no discernable immunosuppressive or toxic effects even after 4 wk of treatment. These observations not only provide insight into the immunoregulatory effects of TGF beta, but also implicate this cytokine as a potentially important therapeutic agent.

Patient evaluation for cardiac transplantation. The aim for cardiac transplantation is to improve the quality of life and the survival in patients with end-stage heart failure. Given the scarcity of donor organ availability, the expense of the transplantation process and follow-up care, as well as the tremendous emotional burden the process places on a patient and his/her family, it is essential to carefully screen potential candidates for their symptomatic, functional, hemodynamic, and psychosocial eligibility, and to rule out coexisting hemodynamic or comorbid conditions that would jeopardize successful transplantation and immunosuppression. Comprehensive screening of potential transplant candidates, which is best accomplished by a multidisciplinary team approach working closely with patients and their families, is essential to insure that maximum benefit is derived from this scarce and valuable resource.

Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. To determine the role of thrombin in high blood flow, platelet-dependent thrombotic and hemostatic processes we measured the relative antithrombotic and antihemostatic effects in baboons of hirudin, a highly potent and specific antithrombin, and compared the effects of heparin, an antithrombin III-dependent inhibitor of thrombin. Thrombus formation was determined in vivo using three relevant models (homologous endarterectomized aorta, collagen-coated tubing, and Dacron vascular graft) by measuring: (1) platelet deposition, using gamma camera imaging of 111In-platelets; (2) fibrin deposition, as assessed by the incorporation of circulating 125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of 1, 5, and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin) maintained constant plasma levels of 0.16 +/- 0.03, 0.79 +/- 0.44, and 3.3 +/- 0.77 mumol/mL, respectively. Hirudin interrupted platelet and fibrin deposition in a dose-dependent manner that was profound at the highest dose for all three thrombogenic surfaces and significant at the lowest dose for thrombus formation on endarterectomized aorta. Thrombotic occlusion was prevented by all doses studied. In contrast, heparin did not inhibit either platelet or fibrin deposition when administered at a dose that maximally prolonged clotting times (100 U/kg) (P greater than .1), and only intermediate effects were produced at 10-fold that dose (1,000 U/kg). Moreover, heparin did not prevent occlusion of the test segments. Hirudin inhibited platelet hemostatic function in concert with its antithrombotic effects (bleeding times were prolonged by the intermediate and higher doses). By comparison, intravenous heparin failed to affect the bleeding time at the 100 U/kg dose (P greater than .5), and only minimally prolonged the bleeding time at the 1,000 U/kg dose (P less than .05). We conclude that platelet-dependent thrombotic and hemostatic processes are thrombin-mediated and that the biologic antithrombin hirudin produces a potent, dose-dependent inhibition of arterial thrombus formation that greatly exceeds the minimal antithrombotic effects produced by heparin.

Inhibition of cell mediated cytotoxicity by sulphasalazine: effect of in vivo treatment with 5-aminosalicylic acid and sulphasalazine on in vitro natural killer cell activity. Decreased cell mediated cytotoxicity occurs frequently in inflammatory bowel disease, particularly in patients with active disease. It is not clear, however, whether this decrease is caused by the disease or is a consequence of the medical treatment. In this study we evaluated the effect of in vivo treatment with 5-aminosalicylic acid and sulphasalazine on the in vitro natural killer cell activity in five patients with inflammatory bowel disease in remission and in four healthy control subjects in a double blind randomised crossover trial preceded and separated by four weeks of treatment with placebo. The natural killer cell activity was significantly impaired in 67% (six of nine subjects) after four weeks' sulphasalazine treatment and tended to be related to subjects with a slow acetylator phenotype. In contrast, 5-aminosalicylic acid treatment caused only a marginal reaction in the natural killer cell activity in 22% (two of nine subjects). The inhibitory effects were found to be reversible since the decreased natural killer cell activity was completely restored after placebo treatment in all subjects. In conclusion, in vivo treatment with sulphasalazine inhibits the in vitro natural killer cell activity and this seems to be mediated by the sulphapyridine moiety. This phenomenon may contribute to the low natural killer cell activity found in patients with active inflammatory bowel disease.

Detection of bcr-abl fusion in chronic myelogeneous leukemia by in situ hybridization. Chronic myelogeneous leukemia (CML) is genetically characterized by fusion of the bcr and abl genes on chromosomes 22 and 9, respectively. In most cases, the fusion involves a reciprocal translocation t(9;22)(q34;q11), which produces the cytogenetically distinctive Philadelphia chromosome (Ph1). Fusion can be detected by Southern (DNA) analysis or by in vitro amplification of the messenger RNA from the fusion gene with polymerase chain reaction (PCR). These techniques are sensitive but cannot be applied to single cells. Two-color fluorescence in situ hybridization (FISH) was used with probes from portions of the bcr and abl genes to detect the bcr-abl fusion in individual blood and bone marrow cells from six patients. The fusion event was detected in all samples analyzed, of which three were cytogenetically Ph1-negative. One of the Ph1-negative samples was also PCR-negative. This approach is fast and sensitive, and provides potential for determining the frequency of the abnormality in different cell lineages.

Mortality in hereditary antithrombin-III deficiency--1830 to 1989 To determine whether antithrombin-III (AT-III) deficiency leads to an excess mortality, we studied 171 individuals from ten families with a proven hereditary deficiency. 73 were classified as certainly deficient either by direct measurement of AT-III concentration or by mendelian inheritance patterns. 98 individuals had a high probability (0.5) of deficiency. The 64 deaths recorded did not exceed those expected for the general population adjusted for age, sex, and calendar period. We suggest that a policy of prophylactic anticoagulation for patients with AT-III deficiency cannot be recommended.

Delayed hearing loss after neurovascular decompression. We report two unusual cases of delayed hearing loss after neurovascular decompression of structures within the cerebellopontine angle. In the first case, the patient noted a unilateral hearing loss 3 weeks after undergoing vascular decompression of the trigeminal nerve for tic douloureux. This gradually improved over an 18-month period. In the second case, the patient awoke on the 4th day after vascular decompression of the facial nerve for hemifacial spasm with a bilateral hearing loss that has remained unchanged after the onset. These are examples of delayed acoustic dysfunction occurring with a shift in surgically freed vessels and may have been induced by newly directed neurovascular compression or distortion.

Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Intraoperative administration of the proteinase inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action, 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 x 10(5) KIU/h during surgery. Additionally, 2 x 10(6) KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1,431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P less than 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P less than 0.05). In the control group, 2.3 +/- 2.2 U of homologous blood or blood products were given, and in the aprotinin group, 0.63 +/- 0.96 U were given (P less than 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly increased until heparin was neutralized after cardiopulmonary bypass (CPB).