Faculty Bibliography

Members of the Quiescin-sulfhydryl oxidase (QSOX) family utilize a thioredoxin domain and a small FAD-binding domain homologous to the yeast ERV1p protein to oxidize sulfhydryl groups to disulfides with the reduction of oxygen to hydrogen peroxide. QSOX enzymes are found in all multicellular organisms for which complete genomes exist and in Trypanosoma brucei, but are not found in yeast. The avian QSOX is the best understood enzymatically: its preferred substrates are peptides and proteins, not monothiols such as glutathione. Mixtures of avian QSOX and protein disulfide isomerase catalyze the rapid insertion of the correct disulfide pairings in reduced RNase. Immunohistochemical studies of human tissues show a marked and highly localized concentration of QSOX in cell types associated with heavy secretory loads. Consistent with this role in the formation of disulfide bonds, QSOX is typically found in the cell in the endoplasmic reticulum and Golgi and outside the cell. In sum, this review suggests that QSOX enzymes play a significant role in oxidative folding of a large variety of proteins in a wide range of multicellular organisms.

This study was undertaken to assess the utility of combined cytokeratin (CK) 7/20 immunoprofile determination in malignant cytologic cell blocks as an aid to the identification of tumor primary site of origin. Fifty-one cases in which CK 7/20 immunocytochemistry was performed as part of the initial workup were retrieved. Their contribution to the final cytologic diagnosis of tumor primary site of origin was analyzed. CK reactivity patterns were 7+/20- (n = 34), 7-/20+ (n = 9), 7-/20- (n = 7), and 7+/20+ (n = 1). The CK 7+/CK 20- immunophenotype was the most common one obtained, and due to its wide expression in a number of common carcinomas, the least informative. The second most common immunophenotype was CK 7-/20+, which is associated with colorectal origin, and as such was very useful when obtained. The CK immunoprofile was more useful in the setting of a prior carcinoma, being a major diagnostic determinant in 13 cases (55%) from group 1 (those with a prior history of malignancy), compared to 8 cases (29%) from group 2 (those with no prior history of malignancy). In the setting of prior carcinoma, the CK immunoprofile is most useful when carcinomas under consideration have different expected immunoprofiles (e.g., CK 7+/CK20- carcinomas, including lung, breast, ovary, endometrium, and others, vs. CK 7-/CK 20+ carcinomas, primarily colorectal). When similar immunoprofiles are obtained, their usefulness is greater if they are immunoprofiles other than the most common 7+/20- pattern. Similarly, in newly diagnosed carcinomas, the CK immunoprofile either helps to narrow the differential diagnosis or points to a specific diagnosis.

BACKGROUND:The stomach contains a wide variety of neuroendocrine cells. Early studies with argyrophilic stains documented the presence of these cells in gastric adenocarcinomas. Immunohistochemical techniques for demonstrating hormones are more sensitive and specific and have been applied only sporadically to gastric adenocarcinomas. Thus, the true incidence of neuroendocrine cells in gastric adenocarcinomas is questionable. METHODS:Formalin-fixed, paraffin-embedded archival tissue specimens from 48 gastric adenocarcinomas were immunostained with antibodies to chromogranin A, synaptophysin, serotonin, gastrin, and neuron-specific enolase. The percentage of cells staining positively was evaluated semiquantitatively. RESULTS:Among 48 gastric adenocarcinomas, 36 (75%) stained positively for chromogranin A, 33 (69%) stained for synaptophysin, 29 (60%) stained for neuron-specific enolase, 17 (36%) stained for gastrin, and 15 (31%) stained for serotonin. The distribution of positivity was highest for chromogranin A (7 cases positive in 26% to 75% of cells) and lowest for serotonin (14 out of 15 cases stained in fewer than 1% of the cells present). CONCLUSIONS:Immunohistochemical evaluation of neuroendocrine markers in gastric adenocarcinomas indicates that a high percentage of tumors contain widely scattered single cells with neuroendocrine differentiation. Most often, however, such cells constitute only a small percentage of the total number of tumor cells present.

We report a case of sepsis due to Clostridium septicum successfully treated with granulocyte colony-stimulating factor (GCSF). This case prompted our review of clostridial sepsis and considerations regarding the use of GCSF in cases of drug-induced neutropenia.

The effect of descending thoracic aortomyoplasty using conditioned latissimus dorsi muscle on cardiac output in five mongrel dogs with pharmacologically induced congestive heart failure was evaluated. A neurovascular left latissimus dorsi flap was lifted and through a left thoracotomy placed around the proximal descending thoracic aorta. The flap was conditioned for 4-6 weeks with a neurostimulator using the following parameters: amplitude 0.5 V, pulse width 210 microseconds and frequency 2 Hz. The neurostimulator was then removed and a cardiomyostimulator inserted and programmed to burst-stimulate the muscle during diastole. Baseline measurements of central venous pressure, heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac output were obtained with the cardiomyostimulator off and on (study 1). Heart failure was induced with a combination of propranolol and verapamil, and measurements again taken with the stimulator off and on. The neurostimulator was reimplanted to continue stimulation of the latissimus dorsi muscle, and another set of measurements taken at 6 weeks with the cardiomyostimulator off and on (study 2). Counterpulsation in control conditions (before cardiac failure) in both studies demonstrated no significant increase in cardiac output. However, mean(s.d.) cardiac output was significantly (P < 0.1) increased by muscle stimulation in dogs with heart failure (study 1: from 2.39(1.10) to 3.14(1.41)l/min; study 2: from 1.89(0.64) to 2.38(0.57)l/min). There was no significant difference in the increase in cardiac output associated with muscle stimulation between studies 1 and 2. The results indicate that the model can increase cardiac output in heart failure and that this improvement is constant over a 4-6 week period, suggesting that muscle fatigue may not occur.

Histopathologic study of skeletal muscle biopsy in a patient with eosinophilia-myalgia syndrome following L-tryptophan use showed prominent lymphocytic perineuritis, neuritis, and perimysial fasciitis. The presence of perineuritis and neuritis provides a histopathologic basis for clinical features of neuropathy in eosinophilia-myalgia syndrome and occurred in conjunction with a fasciitis or interstitial myositis that was predominantly perimysial and focally endomysial.

Experimental animals fed atherogenic diets show endothelial damage, impairment of endothelial regeneration and plasma lipid changes characterized by elevation of LDL and decrease of HDL cholesterol concentrations. Previous studies in this laboratory disclosed that chronic electrical stimulation of the lateral hypothalamus was associated with electron-microscopic evidence of endothelial injury in rats and squirrel monkeys maintained on basal (low fat/cholesterol-free) diets. In the present investigation squirrel monkeys fed similar diets supplemented with "modest" amounts of caloric fat and cholesterol were subjected to chronic lateral hypothalamic stimulation for periods as long as 20 months with the expectation that endothelial injury would be greater than in the absence of the supplements. The expectations were not substantiated. Endothelium was found to be surprisingly intact by electron microscopy and similar to that of implanted nonstimulated controls. A further observation of interest was the cholesterolemic response, notably in the HDL fraction, observed in both groups, but more striking in experimental animals. The data suggest that an interaction between a modified lipid/cholesterol diet and hypothalamic stimulation may lead to elevation of plasma HDL cholesterol concentration and preservation of endothelial integrity. Further investigation is required to determine whether these two events are causally related.

Between 1974 and 1979 nine patients, aged 10 months to 4 years, underwent left ventriculotomy for closure of single or multiple defects in the muscular ventricular septum. The vertical incision paralleled the anterior descending branch of the left coronary artery near the apex of the left ventricle and ranged from 2.5 to 3.5 cm in length. Four patients also had a right ventriculotomy with closure of a high perimembranous ventricular defect in two. Serial electrocardiograms indicated changes of myocardial ischemia or necrosis. Left bundle branch block did not develop in any patient. Three patients died in the early postoperative period. The six surviving patients are living and well 2 to 7 years later. There is apparent complete closure of the ventricular defects, which was documented by cardiac catheterization in four cases. Two patients had cardiomegaly and left ventricular dysfunction as assessed with echocardiographic and angiographic study, whereas four displayed good cardiac function. In three of the latter patients, cardioplegia or deep hypothermia techniques were utilized intraoperatively. The observations indicate that left ventriculotomy of limited size is an acceptable approach to the difficult problem of repair of muscular ventricular defects but may involve some risk of compromise of the coronary circulation.