Mechanism of recovery from systemic vaccinia virus infection. I. The effects of cyclophosphamide.

Administration of Cytoxan in doses capable of inhibiting both humoral and cellular immunity markedly potentiated primary systemic vaccinia virus infection in mice. Immunosuppressed mice did not form neutralizing antibody to vaccinia virus and had a prolonged and more severe viremia than nonimmunosuppressed control mice. Passive transfer of physiologic amounts of neutralizing antibody late in the course of infection, at a time when nonimmunosuppressed mice had similar levels of serum antibody, largely reversed the effect of Cytoxan on vaccinia virus infection. Transfer of 100 million immune spleen cells was much less effective than antibody in reversing the effect of Cytoxan on vaccinia virus infection, and mice receiving these cells did make some antibody. Serum interferon levels were not affected by Cytoxan. The results suggest an essential role for humoral antibody, but not for cellular immunity, in recovery from primary vaccinia virus infection in the mouse.

Age adjusted D-dimer in the Belfast Health and Social Care Trust: A retrospective study.

D-dimers combined with clinical pre-test probability (PTP) scores are used to determine the likelihood of a venous thromboembolic event (VTE). It is recognised that with advancing age, d-dimer values increase, leading to a cohort of patients with a d-dimer above the standard cut-off of 500µg/L. A recent systemic review, examined the accuracy of an age-adjusted D-dimer in those aged > 50 years with a low clinical risk of a VTE. This showed an increase in specificity without loss of sensitivity. Our study, aimed to examine a population of patients, who between 2011 and 2014 underwent ultrasound Doppler studies of lower limbs. By applying a corresponding age-adjusted D-dimer, we determined the sensitivity and specificity and compared this to use of conventional D-dimer.

Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling.

A significant population of humans (5 to 10%) are phenotypic poor metabolizers of debrisoquine. We have isolated the cytochrome P-450 isozyme from rat liver responsible for this activity and have shown that antibodies raised against the protein are able to inhibit this catalytic activity in human liver microsomes (Distlerath, L. M., and Guengerich, F. P., Proc. Natl. Acad. Sci. USA, 81: 7348-7352, 1984). These antibodies were utilized to determine which metabolic transformations are linked to debrisoquine 4-hydroxylation in human liver microsomes using techniques of immunochemical inhibition. The antibodies almost completely inhibited debrisoquine 4-hydroxylation and bufuralol 1'-hydroxylation in microsomes prepared from several different human livers. The oxidation of the pyrrolizidine alkaloids lasiocarpine and monocrotaline were inhibited by roughly one-third. The antibodies did not inhibit N,N-dimethylnitrosamine N-demethylation, oxidation of vinylidene chloride to 2,2-chloroacetaldehyde, oxidation of trichloroethylene to chloral, N-oxidation of azoprocarbazine, morphine N-demethylation, diazepam N-demethylation, oxidation of benzo(a)pyrene to alkali-soluble metabolites, oxidation of benzo(a)pyrene 7,8-dihydrodiol to products covalently bound to DNA, the N- and ring-oxidation of 1- and 2-naphthylamine and 2-aminofluorene, or the conversion of aflatoxin B1 to DNA adducts or aflatoxin Q1. Studies with space-filling models of the drugs the metabolism of which is associated with debrisoquine 4-hydroxylase in the literature indicated that all can be fitted to a general structure in which a basic nitrogen is about 5 A away from the site of carbon hydroxylation and a hydrophobic domain is near the site of hydroxylation. These results may be useful in predicting which chemicals may or may not be metabolized in an atypical manner by a segment of the human population.

Release of interleukin-1 (IL-1) and IL-1-like factors from rabbit macrophages with silica.

Oil-elicited rabbit macrophages stimulated by endotoxin were found to release increased amounts of interleukin 1 (IL-1) when incubated with silica. The assays used to determine the amount of IL-1 released were uptake of thymidine by mouse thymocytes, fever in rabbits, and neutrophilia in rats. All three assays showed that endotoxin-stimulated macrophages released five to 10 times more IL-1 when incubated with silica. Most of the IL-1 had a molecular weight (MW) of about 14,000 with a smaller amount at a MW of approximately 35,000. All of the neutrophilia-producing activity had an isoelectric point (pl) near 7. Thymocyte proliferation was promoted about equally by activities near pH 5 and 7. Fever was found not only at these two isoelectric points but also at a pl above 8 which had neither of the other two activities.

Influence of propranolol isomers and atenolol on myocardial cyclic AMP, high energy phosphates and vulnerability to fibrillation after coronary artery ligation in the isolated rat heart.

The isolated rat heart with ligation of the left coronary artery was used to assess the role of the beta 1- adrenergic receptor-cyclic AMP mechanism in the genesis of vulnerability to ventricular fibrillation in early myocardial ischaemia. Coronary artery ligation was followed after 3 min by a reduction in ventricular fibrillation threshold which reached a minimum at 15 min. This was accompanied by reduction of ATP and phosphocreatine while cyclic AMP was significantly increased in ischaemic myocardium. The dl-, l- and d-isomers of propranolol attenuated the decrease in ventricular fibrillation threshold and the increase in ischaemic myocardial cyclic AMP, without altering the tissue depletion of ATP. Specific beta 1-adrenergic receptor antagonism with atenolol did not prevent either the increase of tissue cyclic AMP or the reduction in ventricular fibrillation threshold and high energy phosphates. These findings suggest that the mechanism whereby vulnerability to fibrillation is increased in very early myocardial ischaemia is linked to changes in cyclic AMP content of ischaemic myocardium and appears independent of depletion of myocardial high energy phosphates.

A case of Balamuthia mandrillaris meningoencephalitis.

Balamuthia mandrillaris is a newly described pathogen that causes granulomatous amebic encephalitis, an extremely rare clinical entity that usually occurs in immunosuppressed individuals. We report a case of pathologically proven Balamuthia encephalitis with unusual laboratory and radiologic findings. A 52-year-old woman with idiopathic seizures and a 2-year history of chronic neutropenia of unknown cause had a subacute illness with progressive lethargy, headaches, and coma and died 3 months after the onset of symptoms. Cerebrospinal fluid (CSF) glucose concentrations were extremely low or unmeasurable, a feature not previously described (to our knowledge). Cranial magnetic resonance imaging scans showed a single large temporal lobe nodule, followed 6 weeks later by the appearance of 18 ring-enhancing lesions in the cerebral hemispheres that disappeared after treatment with antibiotics and high-dose corticosteroids. The initial brain biopsy specimen and analysis of CSF samples did not demonstate amebae, but a second biopsy specimen and the postmortem pathologic examination showed Balamuthia trophozoites surrounded by widespread granulomatous inflammation and vasculitis. The patient's neutropenia and antibiotic use may have caused susceptibility to this organism. Amebic meningoencephalitis should be considered in cases of subacute meningoencephalitis with greatly depressed CSF glucose concentrations and multiple nodular lesions on cerebral imaging. Arch Neurol. 2000;57:1210-1212

Body fat distribution, rather than overall adiposity, influences serum lipids and lipoproteins in healthy men independently of age.

PURPOSE: We investigated the relationships between the amount and distribution of body fat and fasting serum lipids and lipoproteins to explore whether coronary artery disease (CAD) risk may be mediated through effects on the serum lipid profile. PATIENTS AND METHODS: We determined serum total cholesterol and triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and HDL subfractions 2 and 3 in 103 healthy men, aged 21 to 77 years (mean 48.7). The amount and distribution of fat were determined directly by dual energy X-ray absorptiometry. Adiposity was determined as the ratio between total body fat tissue and total body lean tissue, while fat distribution was taken as the ratio between the mass of fat tissue in the android (central) and gynoid (hip and thigh) regions. RESULTS: Univariate analysis showed both adiposity and fat distribution to be correlated with total serum cholesterol and triglyceride concentrations (adiposity r = .20, .21; both P < 0.05: fat distribution r = .25, .38; P < 0.05, P < 0.001, respectively). Fat distribution was also negatively correlated with HDL2 cholesterol (r = -.20, P < 0.05). In multiple linear regression analysis, neither age nor adiposity was significantly correlated with any serum lipid or lipoprotein concentration, while increasing android-to-gynoid ratio was independently associated with elevated total serum triglyceride (r = .40, P < 0.01) and decreased HDL2 (r = -.25, P < 0.05) concentrations. CONCLUSIONS: The association of both age and overall adiposity with the fasting serum lipid profile are mediated via their correlations with body fat distribution. In men, the distribution, rather than the amount, of body fat is related to adverse changes in serum lipids and lipoproteins, and hence potentially to increased CAD risk.

Protective action of amiodarone against ventricular fibrillation in the isolated perfused rat heart.

The pretreatment of rats with amiodarone for 2 minutes to 3 weeks before the excision of their hearts caused a dose-related decrease in heart rate and an increase in the ventricular fibrillation threshold both before and after coronary arterial ligation. Similarly, amiodarone decreased the incidence of ventricular premature extrasystoles, ventricular tachycardia and fibrillation during the period of regional ischemia after coronary arterial ligation and also after reperfusion of the ischemic myocardium. There was no evidence of a metabolic protective effect on ischemic myocardium because tissue high energy phosphate content decreased to a similar extent in ischemic myocardium from control and amiodarone-treated rats. Instead, the protective effect of amiodarone against fibrillation was accompanied by attenuation of the increase in tissue cyclic adenosine monophosphate in ischemic myocardium after coronary arterial ligation. It is proposed that amiodarone exerts a potent antifibrillatory effect by decreasing tissue cyclic adenosine monophosphate in ischemic myocardium.

New solution for prolonged myocardial preservation for transplantation.

BACKGROUND: A solution for prolonged cold storage of the heart has been developed. The Jerusalem-Cape Town Solution (JCT) is an "intracellular" type cardioplegic solution and is formulated to (1) minimize hypothermic-induced cell swelling, (2) diminish intracellular acidosis, (3) prevent the expansion of the interstitial space during the reperfusion, (4) protect against oxygen free radical injury during early reperfusion, and (5) provide substrates for regenerating high-energy phosphates. METHODS: With a Langendorff model, rat hearts were subjected to 15 minutes of perfusion with Krebs-Henseleit, 10 minutes of cardioplegic infusion and 20 hours of cold storage (5 degrees to 6 degrees C). Hearts were reperfused for 60 minutes and hemodynamic recovery was assessed. The hearts were assigned to three groups (eight hearts in each), according to the cardioplegic solution used: group 1, JCT; group 2, Bretschneider's HTK cardioplegic solution; and group 3 University of Wisconsin cold storage solution. RESULTS: After 60 minutes of reperfusion, the recovery of the coronary artery flow in group 1 (JCT) was significantly better than in group 2, and slightly better than in group 3 (64% +/- 8.9%, 47.2% +/- 11.6%, 52.5% +/- 19.9%, mean +/- SD, respectively; group 1 versus group 2, p < 0.01). The recovery of the left ventricular developed pressure (LVDP) was significantly better in group 1 compared with group 2 and group 3 (60.2% +/- 14.5%, 41.1% +/- 12.6% and 36.5% +/- 10.1%, respectively; p < 0.01). The recovery of the heart contractility expressed by the product of LVDP and the heart rate (LVDP x heart rate) was significantly higher in group 1 than in group 2 and group 3 (47.5% +/- 3.4%, 23.6% +/- 9.6%, and 28.7% +/- 8.3%, respectively, p < 0.001). In hearts stored for 12 hours in JCT or HTK, the recovery of the heart contractility did not differ significantly (73.4% +/- 12.7% or 70.8% +/- 30.8%, respectively). Modified reperfusion aimed to improve postischemic heart recovery did not bring significant changes in cardiac mechanical function but resulted in an increase in postischemic coronary artery flow recovery in hearts reperfused with amino acid-enriched buffer. CONCLUSIONS: The JCT solution is effective (as well as HTK) in preserving the ischemic hearts for up to 12 hours. It is superior to HTK or University of Wisconsin solution at 20 hours of isolated ischemic storage.

Effect of continuous combined estrogen and desogestrel hormone replacement therapy on serum lipids and lipoproteins.

OBJECTIVE: To determine the effects of continuous combined hormone replacement therapy with desogestrel and 17 beta-estradiol (E2) on serum lipids and lipoproteins. METHODS: Fifty-seven healthy postmenopausal women of less than 60 years of age were studied prospectively and treated with oral desogestrel 0.15 mg/day and micronized 17 beta-E2 1 mg/day, both taken continuously. Fasting venous blood samples for serum lipids and lipoproteins were taken before and after 6 and 12 months of treatment. RESULTS: Thirty-two women completed the study. Levels of all serum lipids and lipoproteins fell significantly by 6 months and remained low at 12 months. The mean percentage reduction after 12 months of treatment was 12.8% for high-density lipoprotein (HDL) cholesterol, which largely resulted from a reduction in the HDL2 subfraction, which fell by 25.7%. The mean percentage reduction for both low-density lipoprotein (LDL) cholesterol and triglycerides was 7.7%. The median percentage reduction for lipoprotein (a) was 17.6%. CONCLUSIONS: This combination of hormone replacement therapy had profound effects on serum lipids and lipoproteins. According to current concepts, reductions in total and LDL cholesterol, triglycerides, and lipoprotein (a) may reduce cardiovascular disease risk. The reduction in HDL was unexpected, given the rise in HDL that has been demonstrated when desogestrel is combined with ethinyl estradiol in the contraceptive pill. The lowering of HDL observed in this study is undesirable and may be potentially harmful. Our results indicate that when desogestrel 0.15 mg/day is combined with micronized 17 beta-E2 1 mg/day in a continuous manner, the effects of the progestogen on HDL predominate and cause a reduction in HDL and the HDL2 subfraction.

Clostridium difficile colitis mimicking acute peritonitis.

Five patients receiving penicillin V potassium or a cephalosporin antibiotic for 18 hours to 22 days developed fever, marked leukocytosis, and signs and symptoms that suggested right-lower-quadrant peritoneal irritation. All underwent emergency laparotomy, at which dilatation and inflammation of the ascending colon were found. Only one of the patients had profuse diarrhea, and two patients had no diarrhea prior to laparotomy. Postoperatively, Clostridium difficile colitis was diagnosed by stool toxin assay and was confirmed in one case by proctosigmoidoscopic biopsy results. Antibiotic-associated colitis must be considered in any patient who develops peritoneal signs while or after receiving antibiotics. Over a two-year period, the "acute abdomen" presentation accounted for 5.2% of all patients with C difficile colitis at our institutions. Early proctosigmoidoscopy or stool examination for C difficile or its toxin may avoid unnecessary laparotomy in such patients.

Isolated thoracic duct injury after penetrating chest trauma.

BACKGROUND: Isolated thoracic duct injuries as a result of penetrating chest trauma without any major vascular or tracheoesophageal injury seldom are seen. METHODS: A retrospective 13-year review identified 8 patients with this injury. RESULTS: Seven had supraclavicular or suprascapular knife stabs, and the eighth had a low-velocity gunshot injury entering the mid-lateral right chest wall. All 7 stab victims presented with left-sided chylothoraces, and the site of injury of the thoracic duct was within Poirier's triangle, the borders of which are the arch of aorta, the left subclavian artery, and the vertebral column as seen from a lateral approach. Five patients initially were treated conservatively for 13.4 +/- 4.4 days without success. Surgical intervention thus was necessary and was successful in all 8 patients. The thoracic duct injury was controlled successfully through a left posterolateral thoracotomy in 6 patients. A supraclavicular repair was attempted in 1 patient but failed to control the leak and required reexploration via the supraclavicular approach. The right chylothorax from the gunshot injury was explored via a right posterolateral thoracotomy; the leak into the pleura was identified and obliterated. CONCLUSIONS: As conservative management was uniformly unsuccessful, we advocate early operative management through a thoracotomy on the side of the chylothorax for this relatively rare injury.

Surgical relief of acute airway obstruction due to primary tuberculosis.

Primary pulmonary tuberculosis in children remains a leading cause of mortality and morbidity in developing countries. Thirteen children requiring urgent thoracotomy for relief of acute respiratory distress resulting from critical major airway narrowing caused by enlarged tuberculous mediastinal lymph nodes were admitted to two hospitals over a 4-year period. Ages ranged from 2 months to 10 years. The condition of each patient had deteriorated despite appropriate antituberculosis therapy and an oral corticosteroid. At operation, the enlarged tuberculous subcarinal or paratracheal lymph nodes or both were decompressed. Surgical complications included a bronchial tear and a pulmonary artery laceration. Additional procedures included a right upper lobectomy, two pneumonectomies, plication of a hemidiaphragm, and mobilization of two muscle flaps. Postoperatively all children showed dramatic improvement. The trachea to main bronchi diameter ratio improved by 49.1% on the left and 44.9% on the right in the immediate postoperative period. In children with respiratory distress produced by compression of the main bronchi between enlarged subcarinal and paratracheal lymph nodes, surgical decompression of the lymph nodes is indicated if there is no marked initial response to appropriate medical therapy. At operation, lymph nodes should be decompressed only by incision and curettage. Attempts at lymph node excision are associated with increased complications.

Bacteriologic status of necrotic tissue in necrotizing pancreatitis.

To confirm the accuracy of guided percutaneous aspiration (GPA) in distinguishing sterile from infected pancreatic necrosis, we have performed Brown-Brenn tissue Gram stains on pancreatic and peripancreatic necrotic tissue removed operatively in 15 patients. In eight patients judged to have sterile necrosis on the basis of negative cultures of pancreatic exudate obtained first preoperatively (by GPA) and then intraoperatively, necrotic tissue debrided at surgery was also free of bacteria. In seven patients judged to have infected necrosis on the basis of positive cultures of pancreatic exudate obtained first preoperatively (by GPA) and then intraoperatively, necrotic tissue debrided at surgery harbored a considerable number of bacteria. We conclude that GPA targeted to areas of necrosis accurately distinguishes infected necrosis from sterile necrosis, and in infected necrosis, the solid necrotic tissue as well as the fluid component contains bacteria. We therefore believe that infected necrosis is not likely to be eradicated by catheter drainage and should be treated by surgical debridement.

A randomized comparative study of the metabolic effects of two regimens of gestrinone in the treatment of endometriosis.

OBJECTIVE: To study some of the metabolic effects of oral gestrinone on plasma lipoprotein risk markers for cardiovascular disease and on bone density, a risk marker for osteoporosis. DESIGN: Randomized double-blind study. SETTING: All patients were referred to Gynaecology Clinic of Royal Free Hospital Medical School. PATIENTS: Twenty premenopausal women with laparoscopically confirmed endometriosis. INTERVENTIONS: Subjects were randomized in a double-blind fashion to receive either 1.25 mg or 2.5 mg gestrinone two times per week for 6 months. MAIN OUTCOME MEASURE: Laparoscopy was performed before treatment, and clinical responses were determined by second laparoscopy after 6 months. Plasma lipid and bone density measurements during and after therapy were compared with baseline. RESULT: Median total endometriosis scores decreased from 7.5 to 1.0 in the 1.25-mg group and from 7.0 to 0 in the 2.5-mg group. There were no significant between-group differences in endometriosis scores. At both doses, bone density in the spine and the proximal femur was conserved, but plasma concentrations of low-density lipoproteins rose by 13% and those of high-density lipoproteins fell by 40%. CONCLUSIONS: Reducing the dose of gestrinone to 1.25 mg appeared to maintain the therapeutic effectiveness of this treatment but was still associated with potentially unfavorable effects on lipids and lipoproteins.

Sodium transport in hypertension: assessment of membrane-associated defects in South African black and white hypertensives.

Sodium transport was studied in red cells taken from four groups of patients, whites or blacks, and normotensive or hypertensive, with approximately ten patients in each group. There were no differences between normotensive and hypertensive whites. Normotensive blacks had higher rates of sodium-proton exchange than did the other groups, and hypertensive blacks had higher rates of efflux via the sodium-potassium ATPase than did other groups. These data support proposals that hypertension in black subjects is linked to abnormalities of control of intracellular sodium.

Hodgkin' s disease with fulminant non-alcoholic steatohepatitis.

We report a woman with daily febrile episodes who developed fulminant hepatic failure. A percutaneous liver biopsy demonstrated non-alcoholic steatohepatitis, with no evidence of neoplastic infiltration. Post-mortem examination revealed stage IV Hodgkin's disease with trivial liver involvement. Rapidly progressive steatohepatitis causing acute liver failure may be a paraneoplastic presentation of Hodgkin's disease, possibly mediated by cytokines.

Fatal candida pneumonia in a non-immunosuppressed host.

An 83-year-old previously well non-immunosuppressed woman developed invasive fatal candida pneumonia, apparently caused by aspiration. Diagnosis was suggested by the presence of sheets of budding yeasts and pseudohyphae on Gram-stained expectorated sputum and confirmed by an open lung biopsy which demonstrated candida invading lung tissue. Culture of material obtained by open lung biopsy yielded Candida albicans. At autopsy the patient had extensively invasive bilateral candida pneumonia. No other pathogens were isolated from sputum, open lung biopsy or at the time of autopsy. Evidence of disseminated candidiasis was not seen at autopsy. To our knowledge, this is only the fourth documented case of aspiration candida pneumonia in a non-immunosuppressed adult. While candida pneumonia in an immunocompetent adult is very rare, it should be considered in an elderly patient who is not responding to antibiotic therapy. Diagnosis requires aspiration or biopsy of lung, with preferably both histological and cultural evidence of candida infection.

Granulomatous hepatitis in Yersinia enterocolitica bacteraemia.

Bacteraemia caused by Yersinia enterocolitica was associated in a 60-year-old diabetic man with right upper-quadrant abdominal tenderness and abnormal liver function tests. Biopsy of the liver demonstrated granulomas with acute necrosis. To the authors' knowledge, this is the first report of granuloma formation in the human liver associated with this infection. Yersinia enterocolitica should therefore be added to the list of organisms associated with granulomatous hepatitis in human beings.